2-amino-4,5-trisubstituted thiazolyl derivatives

ABSTRACT

This invention concerns the use of a compound of formula (I′) 
                         
a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein Z is halo; C 1-6 alkyl; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; aminocarbonyl; C 1-6 alkyl substituted with hydroxy, carboxyl, cyano, amino, amino substituted with piperidinyl, amino substituted with C 1-4 alkyl substituted piperidinyl, mono- or di(C 1-6 alkyl)amino, aminocarbonyl, mono- or di(C 1-6 alkyl)aminocarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkyloxy, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; polyhaloC 1-4 alkyl; cyano; amino; mono- or di(C 1-6 alkyl)aminocarbonyl; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; aminoS(═O) 2 —; mono- or di(C 1-6 alkyl)aminoS(═O) 2 ; —C(═N—R x )NR y R z ; Q is optionally substituted C 3-6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridyl, or Q is a radical of formula
 
                         
L is optionally substituted phenyl or an optionally substituted monocyclic 5 or 6-membered partially saturated or aromatic heterocycle or a bicyclic partially saturated or aromatic heterocycle; aryl is optionally substituted phenyl; for the manufacture of a medicament for the prevention or the treatment of inflammatory and/or auto-immune diseases mediated through TNF-α and/or IL-12.

This application is a divisional of application Ser. No. 10/486,819,filed Feb. 11, 2004, now U.S. Pat. No. 7,232,838, which in turn is a 371filing and claims the benefit of PCT/EP02/08955, filed on Aug. 9, 2002,which in turn claims the benefit of EP 01203087.0, filed on Aug. 13,2001. The complete disclosures of the aforementioned related U.S. patentapplication is hereby incorporated herein by reference for all purposes.

The present invention concerns 2-amino-4,5-trisubstituted thiazolylderivatives having proinflammatory cytokine production inhibitingproperties, in particular TNF-α and/or IL-12 inhibiting properties. Theinvention further relates to methods for their preparation andpharmaceutical compositions comprising them. The invention also relatesto the use of 2-amino-4,5-trisubstituted thiazolyl derivatives for themanufacture of a medicament for the prevention or the treatment ofdiseases mediated through TNF-α and/or IL-12, especially Il-12.

WO 99/64418 describes aryl-pyridyl thiazoles as TNF-α inhibitors.

WO 02/34748 concerns imidazopyridyl derivatives as anti-tumor agents.

The compounds of the present invention are distinguishable from theprior art because of their structure, pharmacological activity orpotency.

The present invention relates to the use of a compound for themanufacture of a medicament for the prevention or the treatment ofinflammatory and/or auto-immune diseases mediated through TNF-α and/orIL-12, wherein the compound is a compound of formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof,wherein

-   Z is halo; C₁₋₆alkyl; C₁₋₆alkylcarbonyl; aminocarbonyl; C₁₋₆alkyl    substituted with hydroxy, carboxyl, cyano, amino, amino substituted    with piperidinyl, amino substituted with C₁₋₄alkyl substituted    piperidinyl, mono- or di(C₁₋₆alkyl)amino, aminocarbonyl, mono- or    di(C₁₋₆alkyl)aminocarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy,    piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl;    polyhaloC₁₋₄alkyl; cyano; amino; mono- or    di(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyloxycarbonyl;    C₁₋₆alkylcarbonyloxy; amino-S(═O)₂—; mono- or    di(C₁₋₆alkyl)amino-S(═O)₂; or —C(═N—R^(x))NR^(y)R^(z);-   R^(x) is hydrogen, C₁₋₆alkyl, cyano, nitro or —S(═O)₂—NH₂;-   R^(y) is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl;-   R^(z) is hydrogen or C₁₋₆alkyl;-   Q is C₃₋₆cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl,    pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl,    or imidazopyridyl, each of said rings optionally being substituted    with up to three substitutents each independently selected from    halo; hydroxy; cyano; carboxyl; azido; amino; mono- or    di(C₁₋₆alkyl)amino; C₁₋₆alkylcarbonylamino; C₁₋₆alkyl; C₂₋₆alkenyl;    C₂₋₆alkynyl; C₃₋₆cycloalkyl; C₁₋₆alkyl substituted with hydroxy,    C₁₋₆alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino; C₁₋₆alkyloxy;    C₁₋₆alkylthio; C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl;    arylC₁₋₆alkyloxy; aryloxy; polyhaloC₁₋₆alkyl; polyhalo-C₁₋₆alkyloxy;    polyhaloC₁₋₆alkylcarbonyl; Het; C₁₋₄alkyl-S(═O)_(n)— or    R¹HN—S(═O)_(n)—;-   or-   Q is a radical of formula

-   -   wherein X and Y each independently are O, NR³, CH₂ or S, with R³        being hydrogen or C₁₋₄alkyl;        -   q is an integer with value 1 to 4;        -   Z is O or NR⁴ with R⁴ being hydrogen or C₁₋₄alkyl;        -   r is an integer with value 1 to 3;

-   n is an integer with value 1 or 2;

-   R¹ represents hydrogen, or a radical of formula

-   -   with A being O, S or a bivalent radical of formula —CR^(2a)═N—        with CR^(2a) attached to N of formula (a-1); and        -   R^(2a) being hydrogen, C₁₋₆alkyl or C₁₋₆alkyloxy;

-   L is phenyl, optionally substituted with up to 4 substitutents each    independently being selected from halo; hydroxy; mercapto; amino;    cyano; carboxyl; mono- or di(C₁₋₆alkyl)amino; C₁₋₆alkyl; C₁₋₆alkyl    substituted with hydroxy, C₁₋₄alkyloxy, amino or mono- or    di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; aminocarbonyl; mono- or    di(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyl-C(═O)—NH—;    C₁₋₆alkyloxy-C(═O)—NH—; H₂N—C(═O)—NH—; mono- or    di(C₁₋₄alkyl)amino-C(═O)—NH—; Het-NH—; —C(═N—R^(x))NR^(y)R^(z); or

-   L is a monocyclic 5 or 6-membered partially saturated or aromatic    heterocycle or a bicyclic partially saturated or aromatic    heterocycle wherein each of said ring systems may optionally be    substituted with up to 3 substitutents, each substitutent    independently being selected from halo; hydroxy; mercapto; amino;    cyano; carboxyl; mono- or di(C₁₋₆alkyl)amino; C₁₋₆alkyl; C₁₋₆alkyl    substituted with hydroxy, C₁₋₄alkyloxy, amino or mono- or    di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; aminocarbonyl; mono- or    di(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyl-C(═O)—NH—;    C₁₋₆alkyloxy-C(═O)—NH—; H₂N—C(═O)—NH—; mono- or    di(C₁₋₄alkyl)amino-C(═O)—NH—; Het-NH— or —C(═N—R^(x))NR^(y)R^(z);

-   Het is a monocyclic 5 or 6-membered partially saturated or aromatic    heterocycle or a bicyclic partially saturated or aromatic    heterocycle wherein each of said ring systems may optionally be    substituted with up to 3 substitutents, each substitutent    independently being selected from halo; hydroxy; amino; cyano;    carboxyl; mono- or di(C₁₋₆alkyl)amino; C₁₋₆alkyl; C₁₋₆alkyl    substituted with hydroxy, C₁₋₄alkyloxy, amino or mono- or    di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; aminocarbonyl; mono- or    di(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyl-C(═O)—NH—;    C₁₋₆alkyloxy-C(═O)—NH—; H₂N—C(═O)—NH— or mono- or    di(C₁₋₄alkyl)amino-C(═O)—NH—;

-   aryl is phenyl, optionally substituted with up to five substitutents    each independently selected from halo, hydroxy, C₁₋₆alkyl,    polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, cyano, nitro, amino    or mono- or di(C₁₋₆alkyl)amino.

The present invention also relates to a compound of formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof,wherein

-   Z is halo; C₁₋₆alkyl; C₁₋₆alkylcarbonyl; aminocarbonyl; C₁₋₆alkyl    substituted with hydroxy, carboxyl, cyano, amino, amino substituted    with piperidinyl, amino substituted with C₁₋₄alkyl substituted    piperidinyl, mono- or di(C₁₋₆alkyl)amino, aminocarbonyl, mono- or    di(C₁₋₆alkyl)aminocarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy,    piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl;    polyhaloC₁₋₄alkyl; cyano; amino; mono- or    di(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyloxycarbonyl;    C₁₋₆alkylcarbonyloxy; amino-S(═O)₂—; mono- or    di(C₁₋₆alkyl)amino-S(═O)₂ or —C(═N—R^(x))NR^(y)R^(z);-   R^(x) is hydrogen, C₁₋₆alkyl, cyano, nitro or —S(═O)₂—NH₂;-   R^(y) is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl;-   R^(z) is hydrogen or C₁₋₆alkyl;-   Q is C₃₋₆cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl,    pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl,    or imidazopyridyl, each of said rings optionally being substituted    with up to three substitutents each independently selected from    halo; hydroxy; cyano; carboxyl; azido; amino; mono- or    di(C₁₋₆alkyl)amino; C₁₋₆alkylcarbonylamino; C₁₋₆alkyl; C₂₋₆alkenyl;    C₂₋₆alkynyl; C₃₋₆cycloalkyl; C₁₋₆alkyl substituted with hydroxy,    C₁₋₆alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino; C₁₋₆alkyloxy;    C₁₋₆alkylthio; C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl;    arylC₁₋₆alkyloxy; aryloxy; polyhaloC₁₋₆alkyl; polyhalo-C₁₋₆alkyloxy;    polyhaloC₁₋₆alkylcarbonyl; Het; C₁₋₄alkyl-S(═O)_(n)— or    R¹HN—S(═O)_(n)—;    or-   Q is a radical of formula

-   -   wherein X and Y each independently are O, NR³, CH₂ or S, with R³        being hydrogen or C₁₋₄alkyl;        -   q is an integer with value 1 to 4;        -   Z is O or NR⁴ with R⁴ being hydrogen or C₁₋₄alkyl;        -   r is an integer with value 1 to 3;

-   n is an integer with value 1 or 2;

-   R¹ represents hydrogen, or a radical of formula

-   -   with A being O, S or a bivalent radical of formula —CR^(2a)═N—        with CR^(2a) attached to N of formula (a-1); and        -   R^(2a) being hydrogen, C₁₋₆alkyl or C₁₋₆alkyloxy;

-   L is 3-halophenyl or 3-cyanophenyl, each optionally substituted with    1, 2 or 3 substitutents each independently being selected from halo;    hydroxy; mercapto; amino; cyano; carboxyl; mono- or    di(C₁₋₆alkyl)amino; C₁₋₆alkyl; C₁₋₆alkyl substituted with hydroxy,    C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl;    C₁₋₆alkylcarbonyloxy; aminocarbonyl; mono- or    di(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyl-C(═O)—NH—;    C₁₋₆alkyloxy-C(═O)—NH—; H₂N—C(═O)—NH—; mono- or    di(C₁₋₄alkyl)amino-C(═O)—NH—; Het-NH—; —C(═N—R^(x))NR^(y)R^(z); or

-   L is a monocyclic 5 or 6-membered partially saturated or aromatic    heterocycle or a bicyclic partially saturated or aromatic    heterocycle wherein each of said ring systems may optionally be    substituted with up to 3 substitutents, each substitutent    independently being selected from halo; hydroxy; mercapto; amino;    cyano; carboxyl; mono- or di(C₁₋₆alkyl)amino; C₁₋₆alkyl; C₁₋₆alkyl    substituted with hydroxy, C₁₋₄alkyloxy, amino or mono- or    di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; aminocarbonyl; mono- or    di(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyl-C(═O)—NH—;    C₁₋₆alkyloxy-C(═O)—NH—; H₂N—C(═O)—NH—; mono- or    di(C₁₋₄alkyl)amino-C(═O)—NH—; Het-NH— or —C(═N—R^(x))NR^(y)R^(z);

-   Het is a monocyclic 5 or 6-membered partially saturated or aromatic    heterocycle or a bicyclic partially saturated or aromatic    heterocycle wherein each of said ring systems may optionally be    substituted with up to 3 substitutents, each substitutent    independently being selected from halo; hydroxy; amino; cyano;    carboxyl; mono- or di(C₁₋₆alkyl)amino; C₁₋₆alkyl; C₁₋₆alkyl    substituted with hydroxy, C₁₋₄alkyloxy, amino or mono- or    di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; aminocarbonyl; mono- or    di(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyl-C(═O)—NH—;    C₁₋₆alkyloxy-C(═O)—NH—; H₂N—C(═O)—NH— or mono- or    di(C₁₋₄alkyl)amino-C(═O)—NH—;

-   aryl is phenyl, optionally substituted with up to five substitutents    each independently selected from halo, hydroxy, C₁₋₆alkyl,    polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, cyano, nitro, amino    or mono- or di(C₁₋₆alkyl)amino;    provided that the compound is other than    1,2-dihydro-5-[2-[(4-methoxyphenyl)amino]-5-methyl-4-thiazolyl]-6-methyl-2-oxo-3-pyridinecarbonitrile    and    provided that when the bicyclic aromatic heterocycle in the    definition of L represents imidazopyridyl, then said imidazopyridyl    is unsubstituted.

As used hereinabove or hereinafter C₁₋₄alkyl as a group or part of agroup defines straight or branched chain saturated hydrocarbon radicalshaving from 1 to 4 carbon atoms such as methyl, ethyl, propyl,1-methylethyl, butyl; C₁₋₆alkyl as a group or part of a group definesstraight or branched chain saturated hydrocarbon radicals having from 1to 6 carbon atoms such as the groups defined for C₁₋₄alkyl and pentyl,hexyl, 2-methylbutyl and the like; C₂₋₆alkenyl as a group or part of agroup defines straight or branched chain hydrocarbon radicals havingfrom 2 to 6 carbon atoms and having 1 double bond such as ethenyl,propenyl, butenyl, pentenyl, hexenyl, 3-methylbutenyl and the like;C₂₋₆alkynyl as a group or part of a group defines straight or branchedchain hydrocarbon radicals having from 2 to 6 carbon atoms and having 1triple bond such as ethynyl, propynyl, butynyl, pentynyl, hexynyl,3-methylbutynyl and the like; C₃₋₆cycloalkyl is generic to cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl; a monocyclic or bicyclicpartially saturated heterocycle represents a ring system consisting of 1or 2 rings and comprising at least one heteroatom selected from O, N orS, and at least one double bond provided that the ring system is not anaromatic system; a monocyclic or bicyclic aromatic heterocyclerepresents an aromatic ring system consisting of 1 or 2 rings andcomprising at least one heteroatom selected from O, N or S; the termaromatic is well known to a person skilled in the art and designatescyclically conjugated systems of 4n+2 electrons, that is with 6, 10, 14etc. π-electrons (rule of Hückel).

The L or Q radical as described above for the compounds of formula (I)or (I′) may be attached to the remainder of the molecule of formula (I)or (I′) through any ring carbon or heteroatom as appropriate. Forexample, when Q is pyridyl, it may be 2-pyridyl, 3-pyridyl or 4-pyridyl.

Lines drawn into ring systems indicate that the bond may be attached toany suitable ring atom. When the ring system is a bicyclic ring system,the bond may be attached to any suitable ring atom of either of the tworings.

As used herein before, the term (═O) forms a carbonyl moiety whenattached to a carbon atom, a sulfoxide moiety when attached to a sulfuratom and a sulfonyl moiety when two of said terms are attached to asulfur atom.

The term halo is generic to fluoro, chloro, bromo and iodo. As used inthe foregoing and hereinafter, polyhaloC₁₋₄alkyl or polyhaloC₁₋₆alkyl asa group or part of a group is defined as mono- or polyhalosubstitutedC₁₋₄alkyl or C₁₋₆alkyl, for example methyl with one or more fluoroatoms, for example, difluoromethyl or trifluoromethyl, 1,1-difluoroethyland the like. In case more than one halogen atoms are attached to analkyl group within the definition of polyhaloC₁₋₄alkyl orpolyhaloC₁₋₆alkyl, they may be the same or different.

When any variable occurs more than one time in any constituent, eachdefinition is independent.

It will be appreciated that some of the compounds of formula (I) or (I′)and their N-oxides, addition salts, quaternary amines andstereochemically isomeric forms may contain one or more centers ofchirality and exist as stereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore orhereinafter defines all the possible stereoisomeric forms which thecompounds of formula (I) or (I′) and their N-oxides, addition salts,quaternary amines or physiologically functional derivatives may possess.Unless otherwise mentioned or indicated, the chemical designation ofcompounds denotes the mixture of all possible stereochemically isomericforms, said mixtures containing all diastereomers and enantiomers of thebasic molecular structure as well as each of the individual isomericforms of formula (I) or (I′) and their N-oxides, salts, solvates,quaternary amines substantially free, i.e. associated with less than10%, preferably less than 5%, in particular less than 2% and mostpreferably less than 1% of the other isomers. Stereochemically isomericforms of the compounds of formula (I) or (I′) are obviously intended tobe embraced within the scope of this invention.

For therapeutic use, salts of the compounds of formula (I) or (I′) arethose wherein the counterion is pharmaceutically acceptable. However,salts of acids and bases which are non-pharmaceutically acceptable mayalso find use, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove or hereinafter are meant to comprise thetherapeutically active non-toxic acid and base addition salt forms whichthe compounds of formula (I) or (I′) are able to form. Thepharmaceutically acceptable acid addition salts can conveniently beobtained by treating the base form with such appropriate acid.Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric,nitric, phosphoric and the like acids; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e.ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic,fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds of formula (I) or (I′) containing an acidic proton mayalso be converted into their non-toxic metal or amine addition saltforms by treatment with appropriate organic and inorganic bases.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. primary, secondary and tertiary aliphatic and aromaticamines such as methylamine, ethylamine, propylamine, isopropylamine, thefour butylamine isomers, dimethylamine, diethylamine, diethanolamine,dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine,piperidine, morpholine, trimethylamine, triethylamine, tripropylamine,quinuclidine, pyridine, quinoline and isoquinoline; the benzathine,N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids suchas, for example, arginine, lysine and the like.

Conversely the salt form can be converted by treatment with acid intothe free acid form.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) or (I′) as well as the salts thereof,are able to form. Such solvates are for example hydrates, alcoholatesand the like.

The term “quaternary amine” as used hereinbefore defines the quaternaryammonium salts which the compounds of formula (I) or (I′) are able toform by reaction between a basic nitrogen of a compound of formula (I)or (I′) and an appropriate quaternizing agent, such as, for example, anoptionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g.methyliodide or benzyliodide. Other reactants with good leaving groupsmay also be used, such as alkyl trifluoromethanesulfonates, alkylmethanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine hasa positively charged nitrogen. Pharmaceutically acceptable counterionsinclude for example chloro, bromo, iodo, trifluoroacetate and acetate.The counterion of choice can be made using ion exchange resin columns.

The N-oxide forms of the present compounds are meant to comprise thecompounds of formula (I) wherein one or several tertiary nitrogen atomsare oxidized to the so-called N-oxide.

Some of the compounds of formula (I) or (I′) may also exist in theirtautomeric form. Such forms although not explicitly indicated in theabove formula are intended to be included within the scope of thepresent invention.

Particular examples of monocyclic or bicyclic partially saturatedheterocycles are pyrrolinyl, imidazolinyl, pyrazolinyl,2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, indolinyl and the like.

Particular examples of monocyclic or bicyclic aromatic heterocycles areazetyl, oxetylidenyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl,oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, pyranyl, benzofuryl, isobenzofuryl, benzothienyl,isobenzothienyl, indolizinyl, indolyl, isoindolyl, benzoxazolyl,benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl,benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl,purinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinolizinyl,phthalazinyl, quinoxalinyl, quinazolinyl, naphthiridinyl, pteridinyl,benzopyranyl, pyrrolopyridyl, thienopyridyl, furopyridyl,isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl,pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl,furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl,isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl,imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl,furopyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl,isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl,imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl,furopyridazinyl, isothiazolopyridazinyl, thiazolopyridazinyl,isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl,imidazopyridazinyl, oxadiazolopyridyl, thiadiazolopyridyl,triazolopyridyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl,triazolopyrazinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl,triazolopyrimidinyl, oxadiazolopyridazinyl, thiadiazolopyridazinyl,triazolopyridazinyl, imidazooxazolyl, imidazothiazolyl,imidazoimidazolyl, isoxazolotriazinyl, isothiazolotriazinyl,pyrazolotriazinyl, oxazolotriazinyl, thiazolotriazinyl,imidazotriazinyl, oxadiazolotriazinyl, thiadiazolotriazinyl,triazolotriazinyl.

An interesting embodiment of the present invention concerns thosecompounds of formula (I′) or (I) wherein Q is C₃₋₆cycloalkyl, phenyl,pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzthiazolyl,benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridyl, each of saidrings optionally being substituted with up to three substitutents eachindependently selected from halo; hydroxy; cyano; carboxyl; azido;amino; mono- or di(C₁₋₆alkyl)amino; C₁₋₆alkylcarbonylamino; C₁₋₆alkyl;C₂₋₆-alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; C₁₋₆alkyl substituted withhydroxy, C₁₋₆alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino;C₁₋₆alkyloxy; C₁₋₆alkylthio; C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl;arylC₁₋₆alkyloxy; aryloxy; polyhaloC₁₋₆alkyl; polyhalo-C₁₋₆alkyloxy;polyhaloC₁₋₆alkylcarbonyl; C₁₋₄alkyl-S(═O)_(n)— or R¹HN—S(═O)_(n)—;

or

Q is a radical of formula

and wherein Z is halo; C₁₋₆alkyl; C₁₋₆alkylcarbonyl; aminocarbonyl;C₁₋₆alkyl substituted with hydroxy, carboxyl, cyano, amino, mono- ordi(C₁₋₆alkyl)amino, aminocarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy, piperidinyl, piperazinyl,morpholinyl or thiomorpholinyl; polyhaloC₁₋₄alkyl; cyano; amino; mono-or di(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyloxycarbonyl;C₁₋₆alkylcarbonyloxy; amino-S(═O)₂—; mono- or di(C₁₋₆alkyl)amino-S(═O)₂or —C(═N—R^(x))NR^(y)R^(z).

Another interesting embodiment of the present invention concerns thosecompounds of formula (I′) or (I) wherein Q is C₃₋₆cycloalkyl, phenyl,pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzthiazolyl,benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridyl, each of saidrings optionally being substituted with up to three substitutents eachindependently selected from halo; hydroxy; cyano; carboxyl; azido;amino; mono- or di(C₁₋₆alkyl)amino; C₁₋₆alkylcarbonylamino; C₁₋₆alkyl;C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; C₁₋₆alkyl substituted withhydroxy, C₁₋₆alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino;C₁₋₆alkyloxy; C₁₋₆alkylthio; C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl;arylC₁₋₆alkyloxy; aryloxy; polyhaloC₁₋₆alkyl; polyhalo-C₁₋₆alkyloxy;polyhaloC₁₋₆alkylcarbonyl; Het or C₁₋₄alkyl-S(═O)_(n)—; or wherein Q isC₃₋₆cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, orimidazopyridyl, each of said rings optionally being substituted with upto three substitutents each independently selected from halo; hydroxy;cyano; carboxyl; azido; amino; mono- or di(C₁₋₆alkyl)amino;C₁₋₆alkylcarbonylamino; C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl;C₃₋₆cycloalkyl; C₁₋₆alkyl substituted with hydroxy, C₁₋₆alkyloxy, amino,mono- or di(C₁₋₄alkyl)amino; C₁₋₆alkyloxy; C₁₋₆alkylthio;C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl; arylC₁₋₆alkyloxy; aryloxy;polyhaloC₁₋₆alkyl; polyhalo-C₁₋₆alkyloxy; polyhaloC₁₋₆alkylcarbonyl orC₁₋₄alkyl-S(═O)_(n)—.

Also an interesting embodiment of the present invention concerns thosecompounds of formula (I) or (I′) wherein one or more of the followingrestrictions apply:

a) L is 3-halophenyl or 3-cyanophenyl, each optionally substituted with1, 2 or 3 substitutents each independently being selected from halo;hydroxy; mercapto; amino; cyano; carboxyl; mono- or di(C₁₋₆alkyl)amino;C₁₋₆alkyl; C₁₋₆alkyl substituted with hydroxy, C₁₋₄alkyloxy, amino ormono- or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy;C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; aminocarbonyl; mono- ordi(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyl-C(═O)—NH—; C₁₋₆alkyloxy-C(═O)—NH—;H₂N—C(═O)—NH—; mono- or di(C₁₋₄alkyl)amino-C(═O)—NH—; Het-NH—;—C(═N—R^(x))NR^(y)R^(z); in particular L is 3-halophenyl or3-cyanophenyl; orL is a monocyclic 5 or 6-membered partially saturated or aromaticheterocycle or a bicyclic partially saturated or aromatic heterocyclewherein each of said ring systems may optionally be substituted with upto 3 substitutents, each substitutent independently being selected fromhalo; hydroxy; mercapto; amino; cyano; carboxyl; mono- ordi(C₁₋₆alkyl)amino; C₁₋₆alkyl; C₁₋₆alkyl substituted with hydroxy,C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl;C₁₋₆alkyloxy; C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy;aminocarbonyl; mono- or di(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyl-C(═O)—NH—;C₁₋₆alkyloxy-C(═O)—NH—; H₂N—C(═O)—NH—; mono- ordi(C₁₋₄alkyl)amino-C(═O)—NH—; Het-NH— or —C(═N—R^(x))NR^(y)R^(z);b) L is a monocyclic 5 or 6-membered partially saturated or aromaticheterocycle or a bicyclic partially saturated or aromatic heterocyclewherein each of said ring systems may optionally be substituted with upto 3 substitutents, each substitutent independently being selected fromhalo; hydroxy; mercapto; amino; cyano; carboxyl; mono- ordi(C₁₋₆alkyl)amino; C₁₋₆alkyl; C₁₋₆alkyl substituted with hydroxy,C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl;C₁₋₆alkyloxy; C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy;aminocarbonyl; mono- or di(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyl-C(═O)—NH—;C₁₋₆alkyloxy-C(═O)—NH—; H₂N—C(═O)—NH—; mono- ordi(C₁₋₄alkyl)amino-C(═O)—NH—, Het-NH— or —C(═N—R^(x))NR^(y)R^(z);c) Q is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, orimidazopyridyl, each of said rings optionally being substituted with upto three substitutents each independently selected from halo; hydroxy;cyano; carboxyl; azido; amino; mono- or di(C₁₋₆alkyl)amino;C₁₋₆alkylcarbonylamino; C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl;C₃₋₆cycloalkyl; C₁₋₆alkyl substituted with hydroxy, C₁₋₆alkyloxy, aminoor mono- or di(C₁₋₄alkyl)amino; C₁₋₆alkyloxy; C₁₋₆alkylthio;C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl; arylC₁₋₆alkyloxy; aryloxy;polyhaloC₁₋₆alkyl; polyhalo-C₁₋₆alkyloxy; polyhaloC₁₋₆alkylcarbonyl; Hetor C₁₋₄alkyl-S(═O)_(n)—;d) Z is halo; C₁₋₆alkyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl;aminocarbonyl; C₁₋₆alkyl substituted with hydroxy, cyano, amino, aminosubstituted with piperidinyl, amino substituted with C₁₋₄alkylsubstituted piperidinyl, mono- or di(C₁₋₆alkyl)amino, aminocarbonyl,mono- or di(C₁₋₆alkyl)aminocarbonyl, C₁₋₆alkyloxy, piperidinyl,piperazinyl, morpholinyl or thiomorpholinyl; polyhaloC₁₋₄alkyl; cyano;amino; mono- or di(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkylcarbonyloxy;aminoS(═O)₂—; mono- or di(C₁₋₆alkyl)aminoS(═O)₂ or—C(═N—R^(x))NR^(y)R^(z).

Another particular embodiment of the present invention concerns thosecompounds of formula (I) or (I′) wherein one of the followingrestrictions apply:

a) L is a bicyclic partially saturated or aromatic heterocycle otherthan 3,4-dihydro-benzoxazin-3-one wherein each of said ring systems mayoptionally be substituted with up to 3 substitutents, each substitutentindependently being selected from halo; hydroxy; mercapto; amino; cyano;carboxyl; mono- or di(C₁₋₆alkyl)amino; C₁₋₆alkyl; C₁₋₆alkyl substitutedwith hydroxy, C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl;C₁₋₆alkylcarbonyloxy; aminocarbonyl; mono- ordi(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyl-C(═O)—NH—; C₁₋₆alkyloxy-C(═O)—NH—;H₂N—C(═O)—NH—; mono- or di(C₁₋₄alkyl)amino-C(═O)—NH— or Het-NH—;b) L is a bicyclic aromatic heterocycle wherein each of said ringsystems may optionally be substituted with up to 3 substitutents, eachsubstitutent independently being selected from halo; hydroxy; mercapto;amino; cyano; carboxyl; mono- or di(C₁₋₆alkyl)amino; C₁₋₆alkyl;C₁₋₆alkyl substituted with hydroxy, C₁₋₄alkyloxy, amino or mono- ordi(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio;C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; aminocarbonyl; mono- ordi(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyl-C(═O)—NH—; C₁₋₆alkyloxy-C(═O)—NH—;H₂N—C(═O)—NH—; mono- or di(C₁₋₄alkyl)amino-C(═O)—NH— or Het-NH—;c) L is a 6-membered partially saturated or aromatic heterocycle,optionally substituted with up to 3 substitutents, each substitutentindependently being selected from halo; hydroxy; mercapto; amino; cyano;carboxyl; mono- or di(C₁₋₆alkyl)amino; C₁₋₆alkyl; C₁₋₆alkyl substitutedwith hydroxy, C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl;C₁₋₆alkylcarbonyloxy; aminocarbonyl; mono- ordi(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyl-C(═O)—NH—; C₁₋₆alkyloxy-C(═O)—NH—;H₂N—C(═O)—NH—; mono- or di(C₁₋₄alkyl)amino-C(═O)—NH— or Het-NH—;d) L is a 6-membered aromatic heterocycle, optionally substituted withup to 3 substitutents, each substitutent independently being selectedfrom halo; hydroxy; mercapto; amino; cyano; carboxyl; mono- ordi(C₁₋₆alkyl)amino; C₁₋₆alkyl; C₁₋₆alkyl substituted with hydroxy,C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl;C₁₋₆alkyloxy; C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy;aminocarbonyl; mono- or di(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyl-C(═O)—NH—;C₁₋₆alkyloxy-C(═O)—NH—; H₂N—C(═O)—NH—; mono- ordi(C₁₋₄alkyl)amino-C(═O)—NH— or Het-NH—;e) L is a 5-membered partially saturated or aromatic heterocycle,optionally substituted with up to 3 substitutents, each substitutentindependently being selected from halo; hydroxy; mercapto; amino; cyano;carboxyl; mono- or di(C₁₋₆alkyl)amino; C₁₋₆alkyl; C₁₋₆alkyl substitutedwith hydroxy, C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl;C₁₋₆alkylcarbonyloxy; aminocarbonyl; mono- ordi(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyl-C(═O)—NH—; C₁₋₆alkyloxy-C(═O)—NH—;H₂N—C(═O)—NH—; mono- or di(C₁₋₄alkyl)amino-C(═O)—NH— or Het-NH—;f) L is a 5-membered aromatic heterocycle, optionally substituted withup to 3 substitutents, each substitutent independently being selectedfrom halo; hydroxy; mercapto; amino; cyano; carboxyl; mono- ordi(C₁₋₆alkyl)amino; C₁₋₆alkyl; C₁₋₆alkyl substituted with hydroxy,C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl;C₁₋₆alkyloxy; C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy;aminocarbonyl; mono- or di(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyl-C(═O)—NH—;C₁₋₆alkyloxy-C(═O)—NH—; H₂N—C(═O)—NH—; mono- ordi(C₁₋₄alkyl)amino-C(═O)—NH— or Het-NH—.

Also an interesting embodiment of the present invention concerns thosecompounds of formula (I) or (I′) wherein L is optionally substitutedpyridyl, more in particular optionally substituted 3-pyridyl, most inparticular unsubstituted 3-pyridyl.

Another interesting embodiment of the present invention concerns thosecompounds of formula (I) or (I′) wherein Z is halo; C₁₋₆alkyl;C₁₋₆alkylcarbonyl; aminocarbonyl; C₁₋₆alkyl substituted with hydroxy,cyano, amino, amino substituted with piperidinyl, amino substituted withC₁₋₄alkyl substituted piperidinyl, mono- or di(C₁₋₆alkyl)amino,aminocarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy, piperidinyl, piperazinyl,morpholinyl or thiomorpholinyl; polyhaloC₁₋₄alkyl; cyano; amino; mono-or di(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyloxycarbonyl;C₁₋₆alkylcarbonyloxy; amino-S(═O)₂—; mono- or di(C₁₋₆alkyl)amino-S(═O)₂;or —C(═N—R^(x))NR^(y)R^(z).

Another interesting embodiment of the present invention concerns thosecompounds of formula (I) or (I′) wherein Z is halo, in particularfluoro; C₁₋₆alkyl, in particular methyl; C₁₋₆alkyl substituted withamino, in particular —CH₂—NH₂; C₁₋₆alkyl substituted with hydroxy, inparticular —CH(OH)CH₃; C₁₋₆alkyl substituted with amino which issubstituted with piperidinyl, in particular 4-piperidinylaminomethyl;C₁₋₆alkyl substituted with amino which is substituted with C₁₋₄alkylsubstituted piperidinyl, in particular1-methyl-4-piperidinylaminomethyl. A further interesting embodiment ofthe present invention concerns those compounds of formula (I) or (I′)wherein Z is fluoro, methyl or —CH(OH)CH₃.

A further interesting embodiment of the present invention concerns thosecompounds of formula (I) or (I′) wherein Z is fluoro, methyl or—CH(OH)CH₃ and L is a 5- or 6-membered partially saturated or aromaticheterocycle, optionally substituted with up to 3 substitutents, eachsubstitutent independently being selected from halo; hydroxy; amino;cyano; carboxyl; mono- or di(C₁₋₆alkyl)amino; C₁₋₆alkyl; C₁₋₆alkylsubstituted with hydroxy, C₁₋₄alkyloxy, amino or mono- ordi(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio;C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; aminocarbonyl; mono- ordi(C₁₋₆alkyl)aminocarbonyl; C₁₋₆alkyl-C(═O)—NH—; C₁₋₆alkyloxy-C(═O)—NH—;H₂N—C(═O)—NH—; mono- or di(C₁₋₄alkyl)amino-C(═O)—NH— or Het-NH—.

A further interesting embodiment of the present invention concerns thosecompounds of formula (I) or (I′) wherein Q is benzthiazolyl; pyridylsubstituted with halo or C₁₋₆alkyl; phenyl or phenyl substituted withone, two or three substitutents selected from halo, C₁₋₆alkyl,polyhaloC₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, hydroxy, C₁₋₆alkyloxy,C₁₋₆alkylthio, 1-methyl-2-imidazolyl; Z is halo; cyano;C₁₋₆alkylcarbonyl; aminocarbonyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl;C₁₋₆alkyl substituted with hydroxy, C₁₋₆alkyloxy, amino, mono- ordi(C₁₋₆alkyl)amino, piperidinylamino, 1-methyl-4-piperidinylamino ormorpholinyl; L is pyridyl; pyridyl substituted with amino; 3-halophenyl;imidazopyridyl; imidazothiazolyl; pyrimidinyl; furanyl.

Still a further interesting embodiment of the present invention concernsthose compounds of formula (I) or (I′) wherein Q is phenyl,3-trifluoromethyl-phenyl, 3-trifluoromethyl-4-fluoro-phenyl,4-trifluoromethyl-phenyl, 3-bromo-phenyl, 4-bromo-phenyl,4-fluoro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 3-methyl-phenyl,3-hydroxy-phenyl, 4-hydroxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl,3,4-dimethoxy-phenyl, 3,4,5-trimethoxy-phenyl, 3-methylthio-phenyl,4-methyl-phenyl, 2,3-dichloro-phenyl, 3-methyl-4-fluoro-phenyl,3-ethyloxycarbonyl-phenyl, 4-ethyloxycarbonyl-pheny, 6-benzothiazolyl,6-chloro-pyrid-2-yl, 6-methyl-pyrid-2-yl, 5-chloro-pyrid-3-yl,3-trifluoromethyl-4-methoxy-phenyl; Z is bromo, chloro, fluoro, acetyl,aminocarbonyl, ethyloxycarbonyl, morpholinylethyl, morpholinylmethyl,di(methyl)aminoethyl, di(methyl)aminomethyl, ethylaminomethyl,4-piperidinylaminomethyl, 1-methyl-4-piperidinylaminomethyl, —CH(OH)CH₃,aminomethyl, hydroxymethyl, methoxymethyl, cyano, methyloxycarbonyl,methyl; L is 2-amino-5-pyridyl, 3-fluoro-phenyl, 3-pyridyl, 4-pyridyl,3-imidazopyridyl, imidazothiazol-5-yl, 5-pyrimidinyl,5-fluoro-pyrid-3-yl, 3-furanyl.

Also an interesting embodiment of the present invention concerns thosecompounds of formula (I) or (I′) wherein Q is phenyl,3-trifluoromethyl-phenyl, 3-trifluoromethyl-4-fluoro-phenyl,4-trifluoromethyl-phenyl, 3-bromo-phenyl, 4-bromo-phenyl,4-fluoro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 3-methyl-phenyl,4-methoxy-phenyl, 3-methylthio-phenyl, 4-methyl-phenyl,2,3-dichloro-phenyl, 3-methyl-4-fluoro-phenyl,3-ethyloxycarbonyl-phenyl, 4-ethyloxycarbonyl-phenyl, 6-benzothiazolyl,2-chloro-pyrid-5-yl, 2-methyl-pyrid-5-yl, 5-chloro-pyrid-3-yl; Z isfluoro, 4-piperidinylaminomethyl, 1-methyl-4-piperidinylaminomethyl,morpholinylmethyl, —CH(OH)CH₃, aminomethyl, hydroxymethyl, methyl; L is2-amino-5-pyridyl, 3-fluoro-phenyl, 3-pyridyl, 5-fluoro-pyrid-3-yl,3-furanyl, imidazothiazol-5-yl.

Preferred compounds of formula (I) or (I′) are compounds 1, 4 and 14(see Table 1).

In general, compounds of formula (I) wherein Z is halo, said compoundsbeing represented by formula (I-a), can be prepared by reacting anintermediate of formula (II) with an halo-introducing agent of formulahalo-R (III) wherein R represents the remaining of the halo-introducingagent, in the presence of a suitable solvent, such as for exampleN,N-dimethylformamide, optionally in the presence of a suitable base,such as for example 2,6-lutidine. Suitable halo-introducing agents arefor example 1-chloro-pyrrolidinedione, 1-bromo-pyrrolidinedione orSelectfluor®(1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane,bis[tetrafluoroborate(1-)]).

Compounds of formula (I) wherein Z is fluoro, said compounds beingrepresented by formula (I-a-1), can be prepared by reacting anintermediate of formula (IV) wherein W₁ represents a suitable leavinggroup, such as for example chloro, with an intermediate of formula (V)in the presence of a suitable fluoro-introducing agent, such as forexample Selectfluor®, and in the presence of a suitable solvent, such asfor example N,N-dimethylformamide or an alcohol, e.g. ethanol and thelike.

Alternatively, compounds of formula (I-a-1) can also be prepared byreacting an intermediate of formula (XX) with an intermediate of formula(V) in the presence of a suitable solvent, such as for exampletetrahydrofuran.

Compounds of formula (I) wherein Z is C₁₋₆alkyloxycarbonyl orC₁₋₆alkylcarbonyl, said Z being represented by Z_(a), and said compoundsbeing represented by formula (I-b), can be prepared by reacting anintermediate of formula (VI) with an intermediate of formula (V) in thepresence of phenyl N,N,N-trimethylammonium trihalide, e.g. phenylN,N,N-trimethylammonium tribromide, or benzyltrimethylammoniumdichloroiodate and the like, and a suitable solvent, such as for exampletetrahydrofuran or an alcohol, e.g. methanol, ethanol and the like.

Compounds of formula (I) wherein Z is C₁₋₆alkyl or cyano, said Z beingrepresented by Z_(b) and said compounds being represented by formula(I-c), can be prepared by reacting an intermediate of formula (VII)wherein W₂ represents a suitable leaving group, such as for examplehalo, e.g. bromo, with an intermediate of formula (V) in the presence ofa suitable solvent, such as for example an alcohol, e.g. ethanol and thelike.

Compounds of formula (I-c) can also be prepared by reacting anintermediate of formula (VII′) with an intermediate of formula (V) inthe presence of Br₂ or phenyl trimethyl ammonium tribromide and asuitable solvent, such as for example methylene chloride,tetrahydrofuran and an alcohol, e.g. ethanol.

Compounds of formula (I) wherein Z is C₁₋₆alkyl substituted with amino,mono- or di(C₁₋₆alkyl)amino, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, said Z being represented by Z, —C₁₋₆alkyl, and saidcompounds being represented by formula (I-d), can be prepared byreacting an intermediate of formula (VIII) wherein W₃ represents asuitable leaving group, such as for example halo, e.g. chloro, with anintermediate of formula (IX) in the presence of a suitable base, such asfor example NaHCO₃, and a suitable solvent, such as for exampleacetonitrile.

Compounds of formula (I) wherein Z represents CH₂ substituted withpiperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, said Z beingrepresented by formula CH₂—Z_(d) and said compounds being represented byformula (I-e), can be prepared by reacting an intermediate of formula(XVII) with an intermediate of formula (XVIII) in the presence of H₂, asuitable catalyst, such as for example Pt/C, and a suitable solvent,such as for example an alcohol, e.g. methanol.

Compounds of formula (I) wherein Z represents C₁₋₆alkyl substituted withamino, which is substituted with 4-piperidinyl, said compounds beingrepresented by formula (I-f), can be prepared by deprotecting anintermediate of formula (XIX) wherein P represents a suitable protectinggroup, such as for example C₁₋₆alkyloxycarbonyl or benzyloxycarbonyl, inthe presence of a suitable acid, such as for example hydrochloric acidand the like.

The use of protecting groups is fully described in ‘Protective Groups inOrganic Chemistry’, edited by J W F McOmie, Plenum Press (1973), and‘Protective Groups in Organic Synthesis’ 2^(nd) edition, T W Greene & PG M Wutz, Wiley Interscience (1991). Compounds of formula (I) may beconverted into each other following art-known functional grouptransformation reactions, comprising those described hereinafter.

The compounds of formula (I) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.t.butyl hydro-peroxide. Suitable solvents are, for example, water, loweralcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

Compounds of formula (I) wherein L is substituted with amino may beconverted into a compound of formula (I) wherein L is substituted withC₁₋₆alkylcarbonylamino by reaction with a C₁₋₆alkylcarbonyl chloride ina suitable solvent, such as for example pyridine.

Compounds of formula (I) wherein Q is substituted with cyano may beconverted into a compound of formula (I), wherein Q is substituted withcarboxyl by reaction with a suitable acid, such as concentratedhydrochloric acid, in the presence of a suitable reaction-inert solvent,e.g. water.

Compounds of formula (I), wherein L is substituted withC₁₋₆alkyl-C(═O)—NH—, may be converted into a compound of formula (I),wherein L is substituted with amino, by reaction with a suitable acid,such as for example hydrobromic acid and the like, in the presence of asuitable solvent, such as water.

Compounds of formula (I) wherein Z is cyano may be converted into acompound of formula (I) wherein Z is aminocarbonyl by reaction in amixture of H₂SO₄/H₂O.

Compounds of formula (I) wherein Z is cyano may also be converted into acompound of formula (I) wherein Z is —CH₂—NH₂ by reaction with asuitable reducing agent, such as for example H₂, in the presence of asuitable catalyst, such as for example Raney Nickel, and a suitablesolvent, such as for example tetrahydrofuran, NH₃, alcohol, e.g. CH₃OH.

Compounds of formula (I) wherein Z is C₁₋₆alkyloxycarbonyl may beconverted into a compound of formula (I) wherein Z is —CH₂—OH in thepresence of a suitable reducing agent, such as for example LiAlH₄, and asuitable solvent, such as for example tetrahydrofuran.

Compounds of formula (I) wherein Z is C₁₋₆alkylcarbonyl can be convertedinto a compound of formula (I) wherein Z is C₁₋₅alkyl-CHOH— in thepresence of a suitable reducing agent, such as for example NaBH₄ orLiAlH₄, and a suitable solvent, such as for example tetrahydrofuran ordiethyl ether.

Compounds of formula (I) wherein Z is C₁₋₆alkyl substituted with amino,can be converted into a compound of formula (I) wherein Z is C₁₋₆alkylsubstituted with amino which is substituted with piperidinyl orC₁₋₄alkyl substituted piperidinyl, by reaction with piperidine orC₁₋₄alkyl substituted piperidine in the presence of H₂, a suitablecatalyst, such as for example palladium on charcoal, a suitable catalystpoison, such as for example a thiophene solution, and a suitablesolvent, such as for example an alcohol, e.g. methanol and the like.

Compounds of formula (I) wherein Z is C₁₋₆alkyl substituted with amino,can also be converted into a compound of formula (I) wherein Z isC₁₋₆alkyl substituted with dimethylamino, by reaction with paraform inthe presence of H₂, a suitable catalyst, such as for example palladiumon charcoal, a suitable catalyst poison, such as for example a thiophenesolution, and a suitable solvent, such as for example an alcohol, e.g.methanol and the like.

In the following paragraphs, there are described several methods ofpreparing the intermediates in the foregoing preparations. A number ofintermediates and starting materials are commercially available or areknown compounds which may be prepared according to conventional reactionprocedures generally known in the art.

Intermediates of formula (II) can be prepared by reacting anintermediate of formula (IV) with an intermediate of formula (V) in thepresence of a suitable solvent, such as for example an alcohol, e.g.ethanol.

Intermediates of formula (II) can also be prepared by reacting anintermediate of formula (X) with an intermediate of formula (V) in thepresence of phenyl N,N,N-trimethylammonium trihalide, e.g. phenylN,N,N-trimethylammonium tribromide, or benzyl N,N,N-trimethylammoniumdichloroiodate and the like, and a suitable solvent, such as for exampletetrahydrofuran.

Intermediates of formula (IV) can be prepared by reacting L with anintermediate of formula (XI) wherein W₁ is as defined hereinabove, inthe presence C(═S)₂ and AlCl₃.

Intermediates of formula (IV) wherein W₁ is bromo, said intermediatesbeing represented by formula (IV-a) can also be prepared by reacting anintermediate of formula (X) with N,N,N-trimethylbenzenaminium tribromidein the presence of a suitable solvent, such as for exampletetrahydrofuran and an alcohol, e.g. methanol.

Intermediates of formula (V) can be prepared by reacting an intermediateof formula (XII) with a suitable base, such as for example sodiumhydroxide, in the presence of a suitable solvent, such as for example analcohol, e.g. ethanol.

Intermediates of formula (V) can also be prepared by reacting anintermediate of formula (XIII) with benzoyl isothiocyanate in thepresence of a suitable base, such as for example sodium hydroxide, and asuitable solvent, such as for example tetrahydrofuran, or an alcohol,such as for example ethanol.

Intermediates of formula (XII) can be prepared by reacting anintermediate of formula (XIII) with benzoyl isothiocyanate in thepresence of a suitable solvent, such as for example tetrahydrofuran.

Intermediates of formula (VII) wherein Z_(b) represents C₁₋₆alkyl, saidintermediates being represented by formula (VII-a) can be prepared byreacting an intermediate of formula (X′) with a leavinggroup-introducing agent of formula (XIV), such as for example Br₂,wherein R′ represents the remaining part of the leaving groupintroducing agent, in the presence of a suitable acid, such as aceticacid or hydrobromic acid in water.

Intermediates of formula (VII) wherein Z_(b) represents cyano, saidintermediates being represented by formula (VII-b), can be prepared byreacting an intermediate of formula (VII′) wherein Z_(b) representscyano, said intermediates being represented by formula (VII′-a) with anintermediate of formula (XIV) in the presence of a suitable solvent,such as for example methylene chloride.

Intermediates of formula (X′) can be prepared by reacting L with anintermediate of formula (XV) wherein W₁ is defined as hereinabove, inthe presence of AlCl₃ and a suitable solvent, such as for examplemethylene chloride.

Intermediates of formula (VIII) can be prepared by reacting anintermediate of formula (XVI) wherein W₂ and W₃ are as definedhereinabove, with an intermediate of formula (V) in the presence of asuitable solvent, such as for example an alcohol, e.g. methanol.

Intermediates of formula (XVI) wherein W₂ represents bromo, saidintermediates being represented by formula (XVI-a), can be prepared byreacting an intermediate of formula (XXI) with Br₂ in the presence of asuitable acid, such as for example acetic acid and the like.

Intermediates of formula (XXI) wherein W₃ represents chloro andC₁₋₆alkyl represents —(CH₂)₂—, said intermediates being represented byformula (XXI-a), can be prepared by reacting an intermediate of formula(XXII) with HCl.

Intermediates of formula (XVII) can be prepared by reacting a compoundof formula (I-a) with nBuLi in the presence of N,N-dimethylformamide andtetrahydrofuran.

Intermediates of formula (XIX) can be prepared by reacting a compound offormula (I-d) wherein Z represents C₁₋₆alkylNH₂, said compound beingrepresented by formula (I-d-1), with an intermediate of formula (XXIII)in the presence of H₂, a suitable catalyst such as for example palladiumon charcoal, a suitable catalyst poison, such as for example a thiophenesolution, and a suitable solvent, such as for example an alcohol, e.g.methanol and the like.

The compounds of the present invention show cytokine productionmodulating activity, in particular cytokine production inhibitoryactivity, more in particular proinflammatory cytokine productioninhibitory activity. A cytokine is any secreted polypeptide that affectsthe function of other cells by modulating interactions between cells inthe immune or inflammatory response. Examples of cytokines includeInterleukin-1 (IL-1) up to Interleukin-23 (IL-23), Tumor NecrosisFactor-alpha (TNF-α), Tumor Necrosis Factor-beta (TNF-β). The presentcompounds also show inhibitory activity on the production ofchemotacetic cytokines or chemokines responsible for trafficking andactivation of leucocytes. A chemokine production inhibited by thecompounds of formula (I) or (I′) is MCP-1 production (MonocyteChemotacetic Protein 1).

The cytokine production specifically inhibited by the compounds offormula (I) or (I′) is TNF-α and/or Interleukin-12 (IL-12) production.

TNF-α is primarily produced by monocytes, macrophages, T and Blymphocytes, neutrophils, mast cells, tumour cells, fibroblasts,keratinocytes, astrocytes, microglial cells, smooth muscle cells andothers. This proinflammatory cytokine is established at the pinnacle ofproinflammatory cascades; it exerts a key role in the cytokine networkwith regard to the pathogenesis of many infectious, inflammatory andautoimmune diseases. Excessive or unregulated TNF-α production isimplicated in mediating or exacerbating a number of diseases includingrheumatoid arthritis, rheumatoid spondylitis, spondyloarthropathies,systemic lupus erythematosus, osteoarthritis, gouty arthritis, juvenilearthritis and other arthritic conditions, polychondritis, sclerodoma,Wegener granulamatosis, dermatomyositis, Steven-Johnson syndrome,idiopatic sprue, endocrine opthalmopathy, Grave's disease, alveolitis,chronic hypersensitivity pneumonitis, primary billiary cirrhosis,uveitis, keratoconjunctivitis sicca and vernal keratoconjunctivitis,allergic rhinitis, pemphigus, eosinophilia, Loffler's syndrome,eosinophilic pneumonia, parasitic infestation, bronchopulmonaryaspergillosis, polyarteritis nodosa, eosinophilic granuloma,eosinophil-related disorders affecting the airways occasioned bydrug-reaction, sepsis, septic shock, endotoxic shock, gram negativesepsis, toxic shock syndrome, cerebral malaria, adult respiratorydistress syndrome, bronchitis (acute, arachidic, catarrhal, chronic,croupus, phthinoid bronchitis), chronic obstructive airway or pulmonarydisease, pulmonary fibrosis, pneumoconiosis (aluminosis, anthracosis,asbestosis, chalicocis, ptilosis, siderosis, silicosis, tobaccosis,byssionosis), tuberculosis, silicosis, exacerbation of airwayshyperreactivity to other drug therapy (e.g. aspirin or β-agonisttherapy), pulmonary sarcoidosis, bone resorption diseases, meningitis,reperfusion injury, graft versus host reaction, allograft rejections,transplant rejections, fever and myalgias due to infection, such asinfluenza, cachexia (consequential to, e.g. bacterial, viral orparasitic, infection or to deprivation or deterioration of humoral orother organic function, or secondary to malignancy; malarial and vermalcachexia; cachexia resulting from dysfunction of the pituitary, thyroidor thymus glands as well as uremic cachexia; cachexia secondary toacquired immune deficiency syndrome (AIDS)), AIDS, ARC (AIDS relatedcomplex), diabetes, cancer, angiogenesis, lymphoma, Kawasaki syndrome,Behçet's syndrome, aphthous ulceration, skin-related disorders such aspsoriasis, eczema, burns, dermatitis, keloid formation, scar tissueformation, erythema nodosum leprosum, Crohn's disease, ulcerativecolitis, inflammatory bowel disease, irritable bowel syndrome, pyresis,asthma (intrinsic, extrinsic, allergic, non-atopic, exercise induced andoccupational and bacterial infection induced asthma), wheezy infantsyndrome, multiple sclerosis, Parkinson's disease, pancreatitis, cardiacdisease, congestive heart failure, myocardial infarction, acute liverfailure, glomerulonephritis, therapy-associated syndromes comprisingJarisch-Herxheimer reaction, and syndromes associated with IL-2infusion, anti-CD3 antibody infusion, hemodialysis, yellow fevervaccination. TNF-α has also been shown to activate HIV (Human Immunedeficiency Virus) replication in monocytes and/or macrophages.Therefore, inhibition of TNF-α production or activity aids in limitingHIV progression. TNF-α also plays a role in other viral infections, suchas Hepatitis C, CMV (cytomegalovirus), influenza and herpes virusinfections, including herpes simplex virus type-1, herpes simplex virustype-2, varicella-zoster virus, Epstein-Barr virus, human herpesvirus-6, -7 and -8, pseudorabies and rhinotracheitis.

IL-12 is produced primarily by monocytes, macrophages and dendriticcells in response to bacteria, bacterial products (lipopolysaccharide)and immune signals. The production of IL-12 is regulated by othercytokines and endogenous mediators produced during inflammatory andimmunological responses. IL-12 plays a central role in the immunesystem. Evidence obtained from animal models and human diseases suggeststhat inappropriate and protracted production of IL-12 and the ability ofIL-12 to induce the generation of T helper 1 cell type responses may beinstrumental in the development and maintenance of chronic inflammatorydiseases, such as rheumatoid arthritis, collagen induced arthritis,allergic encephalitis, colitis, inflammatory bowel disease, Crohn'sdisease and multiple sclerosis, and in the triggering of autoimmunedisorders, such as diabetes, or graft versus host diseases, shock ormusculoskeletal and connective tissue diseases. The adverse effects alsoinclude anemia (haemolytic, aplastic, pure red cell, idiopaticthrombocytopenia), neutropenia, lymphopenia, hepatosplenomegaly withmononuclear cell infiltration and pulmonary edema with interstitial cellinfiltrates. Excessive IL-12 production may accelerate the inflammatoryprogress of a disease, or the onset of the disease, such as rheumatoidarthritis, or it may also augment the disease severity.

Inhibition of TNF-α and/or IL-12 production by the compounds of formula(I) or (I′) might offer an interesting, potentially less toxicalternative to non-specific immunosuppression (e.g. corticosteroids) inthe treatment of chronic inflammatory and autoimmune diseases. Thecombined modulation of TNF-α and IL-12 production may ameliorate thetreated disease to a greater extent than mono-therapy. The therapeuticeffect of combining the suppression of both the immune and theinflammatory arm of a disease may provide additional clinical benefits.The present compounds are also indicated for use as co-therapeuticagents for use in conjunction with immunosuppressive and/oranti-inflammatory drugs, e.g. as potentiators of the therapeuticactivity of said drugs, to reduce required dosaging or thus alsopotential side effects of said drugs. Immunosuppressive and/oranti-inflammatory drugs include for example cyclopeptide, cyclopeptolideor macrolide immunosuppressive or anti-inflammatory drugs, such as drugsbelonging to the cyclosporin class, e.g. cyclosporine A or G, tacrolimussubstances, ascomycin, rapamycin, glucocorticosteroid drugs, e.g.budesonide, beclamethasone, fluticasone, mometasone.

The compounds of formula (I) or (I′) are useful in preventing ortreating cytokine mediated diseases, and as such, inhibit, suppress orantagonize the production or activity of proinflammatory cytokines, suchas TNF-α and/or IL-12, especially IL-12.

Disorders mediated through TNF-α and/or IL-12 refers to any and alldisorders and disease states in which TNF-α and/or IL-12 play a role,either by the cytokine itself, or by the cytokine causing anothercytokine, such as for example IL-1 or IL-6, or a certain mediator to bereleased.

Due to their cytokine production inhibitory activity, in particulartheir proinflammatory cytokine production inhibitory activity, more inparticular their TNF-α and/or IL-12 inhibitory activity, even more inparticular their IL-12 inhibitory activity, the compounds of formula(I), their N-oxides, pharmaceutically acceptable addition salts,quaternary amines and stereochemically isomeric forms are useful in thetreatment or prevention of diseases or conditions mediated throughcytokines, in particular diseases or conditions related to excessive orunregulated production of proinflammatory cytokines, such as TNF-αand/or IL-12, comprising inflammatory diseases or auto-immune diseases.Diseases or conditions related to an excessive or unregulated productionof proinflammatory cytokines comprise rheumatoid arthritis, rheumatoidspondylitis, spondyloarthropathies, systemic lupus erythematosus,osteoarthritis, gouty arthritis, juvenile arthritis and other arthriticconditions, polychondritis, sclerodoma, Wegener granulamatosis,dermatomyositis, Steven-Johnson syndrome, idiopatic sprue, endocrineopthalmopathy, Graves' disease, alveolitis, chronic hypersensitivitypneumonitis, primary billiary cirrhosis, uveitis, keratoconjunctivitissicca and vernal keratoconjunctivitis, allergic rhinitis, pemphigus,eosinophilia, Loffler's syndrome, eosinophilic pneumonia, parasiticinfestation, bronchopulmonary aspergillosis, polyarteritis nodosa,eosinophilic granuloma, eosinophil-related disorders affecting theairways occasioned by drug-reaction, sepsis, septic shock, endotoxicshock, gram negative sepsis, toxic shock syndrome, cerebral malaria,adult respiratory distress syndrome, bronchitis (acute, arachidic,catarrhal, chronic, croupus, phthinoid bronchitis), chronic obstructiveairway or pulmonary disease, pulmonary fibrosis, tuberculosis,pneumoconiosis (aluminosis, anthracosis, asbestosis, chalicocis,ptilosis, siderosis, silicosis, tobaccosis, byssionosis), exacerbationof airways hyperreactivity to other drug therapy (e.g. aspirin orβ-agonist therapy), silicosis, pulmonary sarcoidosis, bone resorptiondiseases, meningitis, allergic encephalitis, reperfusion injury, graftversus host reaction, allograft rejections, transplant rejections,musculoskeletal and connective tissue diseases, fever and myalgias dueto infection, such as influenza, cachexia (consequential to, e.g.bacterial, viral or parasitic, infection or to deprivation ordeterioration of humoral or other organic function, or secondary tomalignancy; malarial and vermal cachexia; cachexia resulting fromdysfunction of the pituitary, thyroid or thymus glands as well as uremiccachexia; cachexia secondary to acquired immune deficiency syndrome(AIDS)), AIDS, ARC (AIDS related complex), diabetes, cancer,angiogenesis, lymphoma, Kawasaki syndrome, Behçet's syndrome, aphthousulceration, skin-related disorders such as psoriasis, eczema, burns,dermatitis, keloid formation, scar tissue formation, erythema nodosumleprosum, Crohn's disease, ulcerative colitis, inflammatory boweldisease, irritable bowel syndrome, pyresis, asthma (intrinsic,extrinsic, allergic, non-atopic, exercise induced and occupational andbacterial infection induced asthma), wheezy infant syndrome, multiplesclerosis, Parkinson's disease, pancreatitis, cardiac disease,congestive heart failure, myocardial infarction, acute liver failure,glomerulonephritis, therapy-associated syndromes comprisingJarisch-Herxheimer reaction, and syndromes associated with IL-2infusion, anti-CD3 antibody infusion, hemodialysis, yellow fevervaccination, HIV or other viral infections, such as Hepatitis C, CMV,influenza and herpes virus infections, pseudorabies and rhinotracheitis,angiofollicular lympoid hyperplasia, anemia (haemolytic, aplastic, purered cell, idiopatic thrombocytopenia), neutropenia, lymphopenia,hepatosplenomegaly with mononuclear cell infiltration and pulmonaryedema with interstitial cell infiltrates; or to prevent these diseases.In particular, the compounds of formula (I) or (I′) can be used to treatrheumatoid arthritis, Crohn's disease, irritable bowel disease, colitis,psoriasis or multiple sclerosis.

The cytokine production inhibitory activity of the compounds of formula(I) or (I′) such as the inhibition of TNF-α and/or IL-12 production, maybe demonstrated in the in vitro test “Inhibition of cytokine productionin human whole blood cultures”. Suitable in vivo tests are“Determination of cytokine in serum of LPS (lipopolysaccharide) andanti-CD3 challenged mice”, “Inhibition of LPS-galactosamine inducedshock in mice”, “Inhibition of collagen induced arthritis in mice”.

The compounds of formula (I) or (I′) may also inhibit Interleukin-6(IL-6).

The present compounds may also act as intermediates for the preparationof further thiazolyl derivatives.

In view of the above described pharmacological properties, the compoundsof formula (I) or (I′) or any subgroup thereof, their N-oxides,pharmaceutically acceptable addition salts, quaternary amines andstereochemically isomeric forms, may be used as a medicine. Inparticular, the present compounds can be used for the manufacture of amedicament for treating or preventing diseases mediated throughcytokines, more in particular diseases mediated through TNF-α and/orIL-12, such as inflammatory and auto-immune diseases.

In view of the utility of the compounds of formula (I) or (I′), there isprovided a method of treating warm-blooded animals, including humans,suffering from or a method of preventing warm-blooded animals, includinghumans, to suffer from diseases mediated through cytokines, inparticular mediated through TNF-α and/or IL-12, such as inflammatory andauto-immune diseases. Said methods comprise the administration,preferably oral administration, of an effective amount of a compound offormula (I) or (I′), a N-oxide form, a pharmaceutically acceptableaddition salt, a quaternary amine or a possible stereoisomeric formthereof, to warm-blooded animals, including humans.

The present invention also provides compositions for preventing ortreating diseases mediated through cytokines, in particular TNF-α and/orIL-12 comprising a therapeutically effective amount of a compound offormula (I) and a pharmaceutically acceptable carrier or diluent.

The compounds of the present invention or any subgroup thereof may beformulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs. Toprepare the pharmaceutical compositions of this invention, an effectiveamount of the particular compound, optionally in addition salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, particularly, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment. Thecompounds of the present invention may also be administered viainhalation or insufflation by means of methods and formulations employedin the art for administration via this way. Thus, in general thecompounds of the present invention may be administered to the lungs inthe form of a solution, a suspension or a dry powder. Any systemdeveloped for the delivery of solutions, suspensions or dry powders viaoral or nasal inhalation or insufflation are suitable for theadministration of the present compounds.

To aid solubility of the compounds of formula (I), suitable ingredients,e.g. cyclodextrins, may be included in the compositions. Appropriatecyclodextrins are α-, β-, γ-cyclodextrins or ethers and mixed ethersthereof wherein one or more of the hydroxy groups of the anhydroglucoseunits of the cyclodextrin are substituted with C₁₋₆alkyl, particularlymethyl, ethyl or isopropyl, e.g. randomly methylated β-CD;hydroxyC₁₋₆alkyl, particularly hydroxyethyl, hydroxy-propyl orhydroxybutyl; carboxyC₁₋₆alkyl, particularly carboxymethyl orcarboxy-ethyl; C₁₋₆alkylcarbonyl, particularly acetyl. Especiallynoteworthy as complexants and/or solubilizers are β-CD, randomlymethylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD,2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD(2-HP-β-CD).

The term mixed ether denotes cyclodextrin derivatives wherein at leasttwo cyclodextrin hydroxy groups are etherified with different groupssuch as, for example, hydroxy-propyl and hydroxyethyl.

The average molar substitution (M.S.) is used as a measure of theaverage number of moles of alkoxy units per mole of anhydroglucose. Theaverage substitution degree (D.S.) refers to the average number ofsubstituted hydroxyls per anhydroglucose unit. The M.S. and D.S. valuecan be determined by various analytical techniques such as nuclearmagnetic resonance (NMR), mass spectrometry (MS) and infraredspectroscopy (IR). Depending on the technique used, slightly differentvalues may be obtained for one given cyclodextrin derivative.Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125to 10 and the D.S. ranges from 0.125 to 3.

Other suitable compositions for oral or rectal administration compriseparticles consisting of a solid dispersion comprising a compound offormula (I) and one or more appropriate pharmaceutically acceptablewater-soluble polymers.

The term “a solid dispersion” used hereinafter defines a system in asolid state (as opposed to a liquid or gaseous state) comprising atleast two components, in casu the compound of formula (I) and thewater-soluble polymer, wherein one component is dispersed more or lessevenly throughout the other component or components (in case additionalpharmaceutically acceptable formulating agents, generally known in theart, are included, such as plasticizers, preservatives and the like).When said dispersion of the components is such that the system ischemically and physically uniform or homogenous throughout or consistsof one phase as defined in thermo-dynamics, such a solid dispersion willbe called “a solid solution”. Solid solutions are preferred physicalsystems because the components therein are usually readily bioavailableto the organisms to which they are administered. This advantage canprobably be explained by the ease with which said solid solutions canform liquid solutions when contacted with a liquid medium such as thegastro-intestinal juices. The ease of dissolution may be attributed atleast in part to the fact that the energy required for dissolution ofthe components from a solid solution is less than that required for thedissolution of components from a crystalline or microcrystalline solidphase.

The term “a solid dispersion” also comprises dispersions which are lesshomogenous throughout than solid solutions. Such dispersions are notchemically and physically uniform throughout or comprise more than onephase. For example, the term “a solid dispersion” also relates to asystem having domains or small regions wherein amorphous,microcrystalline or crystalline compound of formula (I), or amorphous,microcrystalline or crystalline water-soluble polymer, or both, aredispersed more or less evenly in another phase comprising water-solublepolymer, or compound of formula (I), or a solid solution comprisingcompound of formula (I) and water-soluble polymer. Said domains areregions within the solid dispersion distinctively marked by somephysical feature, small in size, and evenly and randomly distributedthroughout the solid dispersion.

Various techniques exist for preparing solid dispersions includingmelt-extrusion, spray-drying and solution-evaporation.

The solution-evaporation process comprises the following steps

a) dissolving the compound of formula (I) and the water-soluble polymerin an appropriate solvent, optionally at elevated temperatures;

b) heating the solution resulting under point a), optionally undervacuum, until the solvent is evaporated. The solution may also be pouredonto a large surface so as to form a thin film, and evaporating thesolvent therefrom.

In the spray-drying technique, the two components are also dissolved inan appropriate solvent and the resulting solution is then sprayedthrough the nozzle of a spray dryer followed by evaporating the solventfrom the resulting droplets at elevated temperatures.

The preferred technique for preparing solid dispersions is themelt-extrusion process comprising the following steps:

-   -   a) mixing a compound of formula (I) and an appropriate        water-soluble polymer,    -   b) optionally blending additives with the thus obtained mixture,    -   c) heating and compounding the thus obtained blend until one        obtains a homogenous melt,    -   d) forcing the thus obtained melt through one or more nozzles;        and    -   e) cooling the melt till it solidifies.

The terms “melt” and “melting” should be interpreted broadly. Theseterms not only mean the alteration from a solid state to a liquid state,but can also refer to a transition to a glassy state or a rubbery state,and in which it is possible for one component of the mixture to getembedded more or less homogeneously into the other. In particular cases,one component will melt and the other component(s) will dissolve in themelt thus forming a solution, which upon cooling may form a solidsolution having advantageous dissolution properties.

After preparing the solid dispersions as described hereinabove, theobtained products can be optionally milled and sieved.

The solid dispersion product may be milled or ground to particles havinga particle size of less than 600 μm, preferably less than 400 μm andmost preferably less than 125 μm.

The particles prepared as described hereinabove can then be formulatedby conventional techniques into pharmaceutical dosage forms such astablets and capsules.

It will be appreciated that a person of skill in the art will be able tooptimize the parameters of the solid dispersion preparation techniquesdescribed above, such as the most appropriate solvent, the workingtemperature, the kind of apparatus being used, the rate of spray-drying,the throughput rate in the melt-extruder

The water-soluble polymers in the particles are polymers that have anapparent viscosity, when dissolved at 20° C. in an aqueous solution at2% (w/v), of 1 to 5000 mPa·s more preferably of 1 to 700 mPa·s, and mostpreferred of 1 to 100 mPa·s. For example, suitable water-solublepolymers include alkylcelluloses, hydroxyalkyl-celluloses, hydroxyalkylalkylcelluloses, carboxyalkylcelluloses, alkali metal salts ofcarboxyalkylcelluloses, carboxyalkylalkylcelluloses,carboxyalkylcellulose esters, starches, pectines, chitin derivates, di-,oligo- and polysaccharides such as trehalose, alginic acid or alkalimetal and ammonium salts thereof, carrageenans, galactomannans,tragacanth, agar-agar, gummi arabicum, guar gummi and xanthan gummi,polyacrylic acids and the salts thereof, polymethacrylic acids and thesalts thereof, methacrylate copolymers, polyvinylalcohol,polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinylacetate, combinations of polyvinylalcohol and polyvinylpyrrolidone,polyalkylene oxides and copolymers of ethylene oxide and propyleneoxide. Preferred water-soluble polymers are hydroxypropylmethylcelluloses.

Also one or more cyclodextrins can be used as water soluble polymer inthe preparation of the above-mentioned particles as is disclosed in WO97/18839. Said cyclodextrins include the pharmaceutically acceptableunsubstituted and substituted cyclodextrins known in the art, moreparticularly α, β or γ cyclodextrins or the pharmaceutically acceptablederivatives thereof.

Substituted cyclodextrins which can be used to prepare the abovedescribed particles include polyethers described in U.S. Pat. No.3,459,731. Further substituted cyclodextrins are ethers wherein thehydrogen of one or more cyclodextrin hydroxy groups is replaced byC₁₋₆alkyl, hydroxyC₁₋₆alkyl, carboxy-C₁₋₆alkyl orC₁₋₆alkyloxycarbonylC₁₋₆alkyl or mixed ethers thereof. In particularsuch substituted cyclodextrins are ethers wherein the hydrogen of one ormore cyclodextrin hydroxy groups is replaced by C₁₋₃alkyl,hydroxyC₂₋₄alkyl or carboxyC₁₋₂alkyl or more in particular by methyl,ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl orcarboxyethyl.

Of particular utility are the β-cyclodextrin ethers, e.g.dimethyl-β-cyclodextrin as described in Drugs of the Future, Vol. 9, No.8, p. 577-578 by M. Nogradi (1984) and polyethers, e.g. hydroxypropylβ-cyclodextrin and hydroxyethyl β-cyclodextrin, being examples. Such analkyl ether may be a methyl ether with a degree of substitution of about0.125 to 3, e.g. about 0.3 to 2. Such a hydroxypropyl cyclodextrin mayfor example be formed from the reaction between β-cyclodextrin anpropylene oxide and may have a MS value of about 0.125 to 10, e.g. about0.3 to 3.

Another type of substituted cyclodextrins is sulfobutylcyclodextrines.

The ratio of the compound of formula (I) over the water soluble polymermay vary widely. For example ratios of 1/100 to 100/1 may be applied.Interesting ratios of the compound of formula (I) over cyclodextrinrange from about 1/10 to 10/1. More interesting ratios range from about1/5 to 5/1.

It may further be convenient to formulate the compounds of formula (I)in the form of nanoparticles which have a surface modifier adsorbed onthe surface thereof in an amount sufficient to maintain an effectiveaverage particle size of less than 1000 nm.

Useful surface modifiers are believed to include those which physicallyadhere to the surface of the compound of formula (I) but do notchemically bond to said compound.

Suitable surface modifiers can preferably be selected from known organicand inorganic pharmaceutical excipients. Such excipients include variouspolymers, low molecular weight oligomers, natural products andsurfactants. Preferred surface modifiers include nonionic and anionicsurfactants.

Yet another interesting way of formulating the compounds of formula (I)involves a pharmaceutical composition whereby the compounds of formula(I) are incorporated in hydrophilic polymers and applying this mixtureas a coat film over many small beads, thus yielding a composition whichcan conveniently be manufactured and which is suitable for preparingpharmaceutical dosage forms for oral administration.

Said beads comprise a central, rounded or spherical core, a coating filmof a hydrophilic polymer and a compound of formula (I) and optionally aseal-coating layer.

Materials suitable for use as cores in the beads are manifold, providedthat said materials are pharmaceutically acceptable and have appropriatedimensions and firmness. Examples of such materials are polymers,inorganic substances, organic substances, and saccharides andderivatives thereof.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

The present compounds are orally active compounds, and are preferablyorally administered.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) or (I′) used, the particularcondition being treated, the severity of the condition being treated,the age, weight, sex, extent of disorder and general physical conditionof the particular patient as well as other medication the individual maybe taking, as is well known to those skilled in the art. Furthermore, itis evident that said effective daily amount may be lowered or increaseddepending on the response of the treated subject and/or depending on theevaluation of the physician prescribing the compounds of the instantinvention.

The compounds of formula (I) or (I′) may also be used in combinationwith other conventional anti-inflammatory or immunosuppressive agents,such as steroids, cyclooxygenase-2 inhibitors,non-steroidal-anti-inflammatory drugs, TNF-α antibodies, such as forexample acetyl salicylic acid, bufexamac, diclofenac potassium,sulindac, diclofenac sodium, ketorolac trometamol, tolmetine, ibuprofen,naproxen, naproxen sodium, tiaprofen acid, flurbiprofen, mefenamic acid,nifluminic acid, meclofenamate, indomethacin, proglumetacine,ketoprofen, nabumetone, paracetamol, piroxicam, tenoxicam, nimesulide,fenylbutazon, tramadol, beclomethasone dipropionate, betamethasone,beclamethasone, budesonide, fluticasone, mometasone, dexamethasone,hydrocortisone, methylprednisolone, prednisolone, prednisone,triamcinolone, celecoxib, rofecoxib, infliximab, leflunomide,etanercept, CPH 82, methotrexate, sulfasalazine, antilymphocytoryimmunoglobulines, antithymocytory immunoglobulines, azathioprine,cyclosporine, tacrolimus substances, ascomycin, rapamycin,muromonab-CD3.

Thus, the present invention also relates to the combination of acompound of formula (I) or (I′) and another anti-inflammatory orimmunosuppressive agent. Said combination may be used as a medicine. Thepresent invention also relates to a product containing (a) a compound offormula (I) or (I′), and (b) another anti-inflammatory orimmunosuppressive compound, as a combined preparation for simultaneous,separate or sequential use in the treatment of diseases related to anexcessive or unregulated cytokine production. The different drugs may becombined in a single preparation together with pharmaceuticallyacceptable carriers.

EXPERIMENTAL PART

Hereinafter, “DMF” is defined as N,N-dimethylformamide, “DIPE” isdefined as diisopropyl ether, “THF” is defined as tetrahydrofuran.

A. Preparation of the Intermediate Compounds Example A1 a) Preparationof Intermediate 1

AlC₃ (50 g) was added portionwise to a solution ofimidazo[1,2-a]pyridine (0.05 mol) in CS₂ (250 ml). The mixture waswarmed to ±40° C. Then, chloroacetyl chloride (0.11 mol) in CS₂ (50 ml)was added dropwise and the resulting reaction mixture was stirred andrefluxed overnight. The reaction mixture was cooled, then cooled on anice/ethanol-bath and decomposed by dropwise addition of ice-water. CH₃OH(100 ml) was added dropwise and the reaction mixture was stirred for 3hours at room temperature. The resulting precipitate was filtered offand dried (vacuum). Yield: 7.3 g of intermediate 1 (63%).

b) Preparation of Intermediate 2

1-(6-amino-3-pyridinyl)ethanone hydrobromide (0.007 mol) was dissolvedin THF, p.a. (50 ml)/CH₃OH, p.a. (10 ml) and the mixture was stirred atroom temperature. N,N,N-trimethylbenzenaminium tribromide (0.007 mol)was added portionwise and the reaction mixture was stirred overnight atroom temperature. The solvent was evaporated. The residue was stirred in2-propanone/2-propanol, filtered off and dried. Yield: 1.85 g ofintermediate 2 (88.6%).

Example A2 a) Preparation of Intermediate 3

A mixture of 2-bromo-1-(3-pyridinyl)ethanone hydrobromide (0.0030 mol)and [3-(trifluoromethyl)phenyl]thiourea (0.0030 mol) in ethanol (30 ml)was stirred and refluxed for 4 hours, then allowed to cool whilestirring. The mixture was filtered and the filter residue washed withethanol, then 2-propanone. The residue was taken up intoCH₃OH/CH₂Cl₂/(H₂O/Na₂CO₃/NaOAc) and stirred for 10 minutes until mostmaterial had dissolved. The layers were separated. The aqueous phase wasextracted with CH₂Cl₂ (the remaining solid material then dissolved)(×4). The combined organic layers were dried (MgSO₄), filtered and thesolvent was evaporated. Yield: 0.84 g of intermediate 3 (88%; mp:204-206° C.).

b) Preparation of Intermediate 4

1-(3-fluorophenyl)ethanone (0.0082 mol) in THF (50 ml) was stirred atroom temperature. N,N,N-trimethylbenzenaminium tribromide (0.0082 mol)was added portionwise over 1 hour. The formed precipitate was filteredoff and washed. The filtrate was stirred at room temperature.[4-fluoro-3-(trifluoromethyl)phenyl]thiourea (0.0082 mol) was added. Themixture was stirred for 18 hours. The solvent was evaporated. Theresidue was crystallized from CH₃CN (25 ml). The precipitate wasfiltered off, washed with DIPE and dried. Yield: 1.7 g. This fractionwas recrystallized from CH₃CN (25 ml). The precipitate was filtered off,washed with DIPE and dried. Yield: 1.3 g of intermediate 4.

c) Preparation of Intermediate 5

A solution of intermediate 14 (0.005 mol) (prepared according to ExampleA8b), [3-(trifluoromethyl)phenyl]thiourea (0.005 mol) in methanol (50ml) was stirred and refluxed for 14 hours. The reaction mixture wascooled. The precipitate was filtered off and dried. Yield: 1.5 g ofintermediate 5.

Example A3 a) Preparation of Intermediate 6

A solution of benzoyl isothiocyanate (0.068 mol) in THF (50 ml) wasadded dropwise to a solution of 4-fluoro-3-methyl-benzenamine (0.068mol) in THF (150 ml). The reaction mixture was stirred overnight at roomtemperature. The solvent was evaporated. The residue was suspended inDIPE, filtered off, washed and dried (vacuum). Yield: intermediate 6.

b) Preparation of intermediate 7

A mixture of intermediate 6 (0.055 mol) and NaOH 1M (0.06 mol) in EtOH(500 ml) was stirred and refluxed for 1 hour. The reaction mixture wascooled and the solvent was evaporated. The residue was suspended in H₂O,filtered off, washed and dried (vacuum). Yield: 9.8 g of intermediate 7(97%).

Example A4 Preparation of Intermediate 8

A mixture of benzoyl isothiocyanate (0.027 mol) in THF p.a. (10 ml) wasadded dropwise at room temperature to a mixture of 6-benzothiazolamine(0.027 mol) in THF p.a. (80 ml). The mixture was stirred at roomtemperature for 2 hours. The solvent was evaporated. EtOH (100 ml) wasadded to the residue. The mixture was warmed up. NaOH 1M p.a. (0.027mol) was added dropwise. The mixture was stirred while the temperaturewas brought to room temperature. The precipitate was filtered off anddried. Yield: 4 g. The filtrate was evaporated. Yield: 5 g F1. Thefiltered precipitate and F1 were combined and stirred in water. Theprecipitate was filtered off and dried. Yield: 5 g of intermediate 8(88%).

Example A5 a) Preparation of Intermediate 9

A mixture of imidazo[1,2-a]pyridine (0.42 mol) in CH₂Cl₂ (1000 ml) wascooled to 5° C. (ice/EtOH). AlCl₃ (150 g) was added portionwise (temp.rise to 30° C.). A mixture of propanoyl chloride (0.84 mol) in CH₂Cl₂(500 ml) was added dropwise at 10° C. over 30 minutes. The mixture wasstirred and refluxed for 48 hours and then cooled. Ice/MeOH (1000 ml)was added dropwise. The mixture was stirred for 4 hours. The organiclayer was separated and the solvent was evaporated. The residue wasstirred in 2-propanone, filtered and dried in vacuo at 40° C. Yield:64.79 g of intermediate 9 (73%).

b) Preparation of Intermediate 10

HBr 48% in H₂O (50 ml) was added to a mixture of intermediate 9 (0.095mol) in HOAc (150 ml). The mixture was warmed up to 70° C. Br₂ (0.095mol) was added dropwise. The mixture was stirred for 14 hours at 70° C.and then cooled. The solvent was evaporated. The residue wasco-evaporated with EtOH/toluene. The residue was stirred in 2-propanone.The precipitate was filtered off and dried at 40° C. in vacuo. Theresidue (12.682 g) was stirred in refluxing 2-propanone. EtOH was addeduntil the reaction mixture was homogeneous. The mixture was allowed tocool. The precipitate was filtered off and dried in vacuo at 50° C.Yield: 100% of intermediate 10.

Example A6 Preparation of Intermediate 11

Reaction under N₂ atmosphere. A mixture of sodiumβ-oxo-3-pyridinepropanenitrile ion (1⁻) (0.005 mol) in CH₂Cl₂, p.a. wasstirred at −70° C. Br₂ (0.005 mol) in CH₂Cl₂, p.a. (10 ml) was addeddropwise over 30 minutes at −70° C. The mixture was allowed to warm toroom temperature. The mixture was stirred overnight at 20° C. CH₂Cl₂(100 ml) was added. The mixture was filtered and the filtrate wasevaporated (at low temperature). Yield: 1 g (91%) of intermediate 11.

Example A7 Preparation of Intermediate 12

A mixture of compound 99 (0.0141 mol) in tetrahydrofuran (125 ml) wasstirred under N₂ on an isopropanol/CO₂ cooling bath. Tetrahydrofuran(100 ml) was added and stirring was continued till a temperature of −78°C. nBuLi was added dropwise. After addition, the reaction mixture wasstirred further at −78° C. for at least 1 hour, then DMF (11 ml) wasadded dropwise. After addition, stirring was continued at −78° C. foranother hour. Then, the reaction mixture was allowed to reach −15° C.and 100 ml of HCl 1N+100 ml of ice water was added dropwise. Afteraddition, stirring was continued for 30 minutes followed by extractionwith 500 ml of ethyl acetate. K₂CO₃ was added to the separated aqueouslayer till a pH of approximately 9 was reached and the mixture was againextracted with 100 ml of ethyl acetate. The combined organic layers weredried (MgSO₄), filtered and evaporated. The residue was stirred in 50 mlof boiling acetonitrile/CH₂Cl₂ 3/1. The residue was filtered off, washedwith acetonitrile and dried at 50° C. (vacuum). Yield: 3.08 g ofintermediate 12.

Example A8 a) Preparation of Intermediate 13

(0.14 mol) and HCl 12 N (240 ml) were stirred and refluxed. The solventwas evaporated and the residue was taken up in ice/CH₂Cl₂. The mixturewas alkalized with Na₂CO₃. The organic layer was separated, washed withH₂O, dried, filtered and evaporated. The residue was purified on SiO₂(eluent: CH₂Cl₂/CH₃OH). The desired fraction was evaporated. Yield: 15 gof intermediate 13.

b) Preparation of Intermediate 14

Br₂ (0.08 mol) was added dropwise to a mixture of intermediate 13 (15 g)and acetic acid (60 ml) and stirring was continued overnight at roomtemperature. The solvent was evaporated and the residue was crystallizedfrom diisopropyl ether. The precipitate was filtered off and dried.Yield: 14 g of intermediate 14.

Example A9 Preparation of Intermediate 15

A solution of compound 93 (0.00122 mol) and1-tert.butoxycarbonyl-4-piperidinone (0.3 g) in thiophene solution (0.1ml) and methanol (50 ml) was hydrogenated with H2 (1 eq.) over Pd/C 10%(0.1 g). The catalyst was filtered off. The filtrate was evaporated andco-evaporated with toluene. The residue was purified over silica usingCH₂Cl₂/MeOH 96/4 as eluent. The desired fractions were combined andevaporated. The solid was crystallized from 10 ml of diisopropyl ether,filtered off, washed and dried at 50° C. (vacuum). Yield: 0.276 g ofintermediate 15.

B. Preparation of the Final Compounds Example B1 a) Preparation ofCompound 11

Intermediate 3 (0.016 mol) was dissolved in DMF (40 ml), cooled to 5° C.and then 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis[tetrafluoroborate(1⁻)] (=Selectfluor®) (0.017 mol) was added in oneportion. The reaction mixture was stirred and allowed to warm slowly toroom temperature and stirred further for 24 hours. A NH₃/MeOH-solutionand H₂O was added while rapid stirring and cooling and the mixture wasstirred for 6 hours. The mixture was poured out into H₂O (100 ml),filtered and washed with H₂O. The residue was purified by flash columnchromatography over silica gel (eluent: THF/hexane 20/80). The productfractions were collected and the solvent was evaporated. The residue wasdried (24 hours, 20° C., vacuum). Yield: 2.19 g of compound 1 (40%; mp208-210° C.).

b) Preparation of Compound 2

Intermediate 3 (0.0026 mol) was dissolved in DMF (10 ml), then cooled to±0° C. 1-Chloro-2,5-pyrrolidinedione (0.0026 mol) was added in one shot.The reaction mixture was stirred for 2 hours, allowing to warm to roomtemperature. The solvent was evaporated. The residue was trituratedunder water+Na₂CO₃ (aq.), filtered off, washed with water, CH₃CN, thendissolved in ethanol (150 ml). The solution was filtered and thefiltrate was acidified (to pH=1) with HCl/2-propanol. The solvent wasevaporated. Yield: 0.30 g of compound 2 (29%).

In order to prepare 5-bromo derivatives, such as compound 99,1-bromo-2,5-pyrrolidinedione can be used.

c) Preparation of Compound 3

(0.03 mol, crude residue, containing Br⁻)(prepared according to A2a) inDMF (50 ml) was stirred until dissolution. Selectfluor® (0.003 mol) wasadded portionwise and the mixture was stirred overnight at roomtemperature. The solvent was evaporated and coevaporated with toluene.The residue was stirred in toluene. The precipitate was filtered off anddried. Yield: 1.2 g. The filtrate was purified by column chromatographyover silica gel (eluent: CH₂Cl₂/MeOH 98/2; 90/10). The desired fractionswere collected and the solvent was evaporated. The residue wasrecrystallized from CH₃CN. The precipitate was filtered off and dried.Yield: 0.34 g. This fraction was dried overnight (80-90° C.; vacuum).Yield: 0.3 g of compound 3.

Example B2 a) Preparation of Compound 5

1-(3-Pyridinyl)-1,3-butanedione (0.01 mol) in THF (200 ml) was stirred.N,N,N-trimethylbenzenaminium tribromide (0.01 mol) was added portionwiseat 20° C. The mixture was stirred for 45 minutes. EtOH (100 ml) wasadded and the mixture was stirred for 15 minutes.[3-(Trifluoromethyl)phenyl]thiourea (0.01 mol) was added. The mixturewas stirred overnight at 20° C.; then stirred and refluxed. The mixturewas stirred for 1 hour. The precipitate was filtered off and dried.Yield: 0.6 g. The filtrate's solvent was evaporated. The residue wascrystallized from 2-propanol. The precipitate was filtered off anddried. Yield: 1.5 g of compound 5 (34%).

b) Preparation of Compound 6

A mixture of 2-bromo-1-(3-pyridinyl)-1-propanone hydrobromide (0.005mol) and [3-(trifluoro)phenyl]thiourea (0.005 mol) in EtOH (50 ml) wasstirred and refluxed for 8 hours. The reaction mixture was cooled,filtered, washed with EtOH and 2-propanone and then dried (60° C.,vacuum, 16 hours). Yield: 1.52 g of compound 6 (73%).

c) Preparation of compound 7

A mixture of intermediate 11 (0.007 mol) and (4-fluorophenyl)thiourea(0.008 mol) in ethanol (150 ml) was stirred and refluxed for 4 hours,then stirred overnight at 20° C. The precipitate was filtered off,washed with 2-propanol, and dried. Yield: 0.8 g of compound 7 (30%).

d-1) Preparation of Compound 8

A mixture of sodium β-oxo-3-pyridinepropanenitrile ion (1⁻) (0.029 mol)in CH₂Cl₂, p.a. (100 ml) was stirred at −60° C. A solution of Br₂ (0.029mol) in CH₂Cl₂, p.a. (20 ml) was added dropwise at −60° C. and thereaction mixture was allowed to warm to room temperature. A solution of(4-fluorophenyl)thiourea (0.029 mol) in CH₂Cl₂, p.a. (50 ml) was added.Ethanol (100 ml) was added and the reaction mixture was stirredovernight. The solvent was evaporated. The residue was stirred in2-propanol, filtered off, stirred in NH₄OH, filtered off and dried.Yield: 4.2 g of compound 8.

d-2) Preparation of Compound 96

To a stirring mixture of sodium β-oxo-3-pyridinepropanenitrile ion (1⁻)(0.088 mol) and tetrahydrofuran (250 ml) under N₂ atmosphere, phenyltrimethyl ammonium tribromide ((0.088 mol) was added portionwise. Afteraddition, the reaction mixture was stirred further for 3 hours at roomtemperature. (4-fluoro-3-trifluoromethyl-phenyl)thiourea (0.084 mol) wasadded followed by the addition of ethanol (100 ml). The reaction mixturewas stirred further at room temperature for 3 hours, refluxed for 3hours and stirred further at room temperature for 16 hours.Tetrahydrofuran (150 ml) was added and stirring continued for 1 hour.The mixture was filtered and the residue washed with tetrahydrofuran.The residue was then stirred in boiling acetonitrile (75 ml)/H₂O (100ml)/NaHCO₃ aqueous saturated solution (50 ml) for 30 minutes. Themixture was filtered at 35° C., the residue washed with acetonitrile-H₂O(½), with H₂O, with ethanol and with diisopropyl ether. The residue wasdried at 60° C. (vacuum). Yield: 11.74 g of compound 96.

Example B3 Preparation of Compound 9

A mixture of

(interm. 5; prepared according to A2.c) (0.0025 mol),N-methylmethanamine hydrochloride (0.003 mol) and NaHCO₃ (0.01 mol) inCH₃CN (25 ml) was stirred overnight at 50° C. More N-methylmethanaminehydrochloride (0.012 mol) and NaHCO₃ (0.0125 mol) were added and themixture was stirred at 70° C. for 48 hours (in pressure tube). Themixture was cooled. The solvent was evaporated. The residue wasdissolved in CH₂Cl₂ and washed with H₂O. The separated organic layer wasdried, filtered and the solvent was evaporated. The residue was purifiedby column chromatography over silica gel (eluent: CH₂Cl₂/MeOH 98/2). Thedesired fractions were collected and the solvent was evaporated. Theresidue was triturated under DIPE. The precipitate was filtered off anddried. Yield: 0.1 g of compound 9.

Example B4 Preparation of Compound 10

H₂SO₄/H₂O 90/10 (50 ml) was stirred in a reaction flask. Then, compound84 (prepared according to B2.c) (0.0082 mol) was added portionwise at20° C. The reaction mixture was heated to ±70° C., then stirredovernight at 20° C. The mixture was re-heated and stirred for one hourat 70° C., then for 3 hours at 20° C. The mixture was poured out ontoice and this mixture was alkalized with a NH₄OH (conc.) and leftovernight. The precipitate was filtered off, washed with H₂O and dried.The residue was crystallized from DMF/methanol, filtered off and dried.Yield: 1.5 g of compound 10.

Example B5 Preparation of Compound 11

A mixture of compound 8 (prepared according to B2.d) (0.014 mol) inNH₃/CH₃OH (150 ml) and THF (50 ml) was hydrogenated at 14° C. with RaneyNickel (catalytic quantity). After uptake of H₂ (2 equiv), the catalystwas filtered off and the filtrate was evaporated. The residue wasstirred in 2-propanol, filtered off and dried. Yield: 2.8 g. Part (0.5g) of this fraction was purified by column chromatography over silicagel (eluent: CH₂Cl₂/CH₃OH 97/3). The product fractions were collectedand the solvent was evaporated. The residue was dried. Yield: 0.4 g ofcompound 11.

Example B6 Preparation of Compound 13

LiAlH₄ (0.007 mol) was suspended in THF (100 ml) and stirred at roomtemperature. Compound 12 (prepared according to B2.a) (0.0034 mol) wasadded and the mixture was stirred for 2 hours at room temperature. H₂O(5 ml) was added dropwise. NaOH (1N; 10 ml) was added dropwise. H₂O (50ml) was added dropwise. The mixture was filtered over dicalite. Thesolvent was evaporated. The residue was taken up in CH₂Cl₂ and H₂O. Theseparated organic layer washed with H₂O, dried and filtered. The solventwas evaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/MeOH 99/1). The desired fractions werecollected and the solvent was evaporated. The residue was triturated.The precipitate was filtered off and dried. Yield: 0.1 g of compound 13.

Example B7 Preparation of Compound 14

NaBH₄ (0.015 mol) was slowly added in 30 minutes at 20° C. to a mixtureof compound 5 (prepared according to B2.a) (0.0034 mol) in methanol (100ml). The mixture was stirred overnight. More NaBH₄ (0.5 g) was addeddropwise at 20° C. Again the mixture was stirred overnight at 20° C. Thereaction mixture was filtered, washed with water and then dried. Yield:1.6 g of compound 15.

Example B8 a) Preparation of Compound 89

A mixture of compound 93 (0.2 g; 0.0005 mol), 1-methyl-4-piperidinone(0.1 g), Pd/C 10% (0.1 g), thiophene solution (0.1 ml) and methanol (50ml) was stirred for 7 days at room temperature under H₂ (0.0005 mol).1-methyl-4-piperidinone was added several times. The catalyst wasfiltered off, the residue was filtered over silica gel (eluent:CH₂Cl₂/CH₃OH/CH₃OH—NH₃ 95/5/0 to 90/10/0 to 90/5/0). The desiredfractions were collected, the solvent was evaporated. The residue waspurified by column chromatography (eluent: CH₂Cl₂/CH₃OH—NH₃ 95/5). Thedesired fractions were collected, the solvent was evaporated and theresidue was dried. Yield: 0.044 g of compound 89.

b) Preparation of Compound 90 and Compound 91

A mixture of compound 93 (0.5 g; 0.00135 mol), paraform (0.85 g), Pd/C10% (0.9 g), thiophene solution (1 ml) and methanol (50 ml) was stirredat room temperature under H₂ (0.0027 mol). After 24 hours the catalystwas filtered off and the filtrate was evaporated. The residue waspurified by column chromatography (eluent: CH₂Cl₂/CH₃OH—NH₃: 98/2 to95/5). Two fractions (F1, F2) were collected. The solvent of F1 wasevaporated, the residue was stirred in diisopropyl ether, filtered offand dried. Yield: 0.069 g of compound 90. The solvent of F2 wasevaporated, the residue was stirred in CH₂Cl₂, filtered off and dried.Yield: 0.023 g of compound 91.

Example B9 Preparation of Compound 100 and Compound 101

A mixture of intermediate 12 (0.0008 mol) and morpholine (0.006 mol) inmethanol (50 ml) was hydrogenated at room temperature for 4 days withPt/C₅% as a catalyst. After uptake of H₂ (1 equiv.), the catalyst wasfiltered off and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/MeOH 95/5)yielding two fractions. The two fractions were collected and the solventwas evaporated yielding residue I and II. Residue I was stirred indiisopropyl ether. The precipitate was filtered off and dried. Yield0.079 g of compound 100. Residue II was dried. Yield: 0.056 g ofcompound 101.

Example B10 Preparation of Compound 88

To a stirring solution of intermediate 15 (0.0005 mol) in isopropanol(10 ml) was added HCl 6 N in isopropanol (2 ml). The reaction mixturewas stirred at 100° C. for 3½ hours and was then allowed to cool to roomtemperature. The solvent was evaporated. The residue was stirred in 10ml of NaHCO₃ aqueous saturated solution+5 ml of H₂O for 1 hour. Theprecipitate was filtered off, washed with H₂O and dried at 50° C. Yield:0.170 g of compound 88.

Table 1 lists compounds of formula (I) as prepared according to one ofthe above examples (Ex. No.).

TABLE 1 Comp. Ex. Phys. No. No. L Z Q properties 3 B1c

Br

•acetate(1:1) 15 B1c

Br

5 B2a 3-pyridyl —C(═O)CH₃

•HBr(1:1) 16 B4 3-pyridyl —C(═O)NH₂

10 B4 3-pyridyl —C(═O)NH₂

17 B3 3pyridyl

14 B7 3-pyridyl —CH(OH)CH₃

18 B5 3-pyridyl —CH₂NH₂

•HCl(1:2) 11 B5 3-pyridyl —CH₂NH₂

19 B6 4-pyridyl —CH₂OH

13 B6 3-pyridyl —CH₂OH

2 B1b 3-pyridyl Cl

•HCl(1:1) 20 B1b

Cl

21 B1b 3-pyridyl Cl

22 B1b 3-pyridyl Cl

23 B1a

F

•HCl(1:1)•H₂O (1:1) m.p.: 180° C. 24 B1a 3-pyridyl F

m.p.: 226° C. 25 B1a

F

4 B1a

F

m.p.: 210- 215° C. 1 B1a 3-pyridyl F

26 B1a

F

27 B1a 3-pyridyl F

28 B1a

F

29 B1a

F

•HCl(1:1) 30 B1a 3-pyridyl F

31 B1a 3-pyridyl F

m.p.: 176- 178° C. 32 B1a

F

•HCl(1:1) 33 B1a 3-furyl F

34 B1a 3-pyridyl F

•HBr(1:2) 35 B1a

F

36 B1a 3-pyridyl F

37 B2b

CH₃

•HBr(1:2) 38 B2b 3-pyridyl CH₃

•HBr(1:2) 39 B2b 4-pyridyl CH₃

•HBr(1:2) 40 B2b

CH₃

•HBr(1:1) 41 B2b 3-pyridyl CH₃

•HBr(1:1) 42 B2b 4-pyridyl CH₃

•HBr(1:2) 43 B2b 3-pyridyl CH₃

•HBr(1:2) 44 B2b 3-pyridyl CH₃

45 B2b

CH₃

•HBr(1:1) 6 B2b 3-pyridyl CH₃

•HBr(1:1) 46 B2b 3-pyridyl CH₃

•HBr(1:2) 47 B2b

CH₃

•HBr(1:1) 48 B2b 3-pyridyl CH₃

•HBr(1:2) 49 B2b 4-pyridyl CH₃

•HBr(1:1) 50 B2b 3-pyridyl CH₃

51 B2b 3-pyridyl CH₃

52 B2b

CH₃

53 B2b 3-pyridyl CH₃

54 B2b 3-pyridyl CH₃

55 B2b 3-pyridyl CH₃

56 B2b 3-pyridyl CH₃

57 B2b 3-pyridyl CH₃

58 B2b

CH₃

59 B2b 3-pyridyl CH₃

60 B2b 3-pyridyl CH₃

61 B2b

CH₃

62 B2b 3-pyridyl CH₃

•HBr(1:1) 63 B2b 3-pyridyl CH₃

64 B2b

CH₃

•HBr(1:2) 65 B2b 3-pyridyl CH₃

•HBr(1:2) 66 B2b 4-pyridyl CH₃

•HBr(1:1) 67 B2b 3-pyridyl CH₃

68 B2b

CH₃

69 B2b 3-pyridyl CH₃

70 B2b

CH₃

71 B2b 3-pyridyl CH₃

72 B2b 3-pyridyl CH₃

73 B2b

CH₃

74 B2b 3-pyridyl CH₃

75 B2b

CH₃

76 B2b 3-pyridyl CH₃

77 B2b

CH₃

78 B2b 3-pyridyl CH₃

79 B2b

CH₃

80 B2b 3-pyridyl CH₃

81 B2a 4-pyridyl CH₃—CH₂—O—C(═O)—

9 B3 3-pyridyl (CH₃)₂N—CH₂—CH₂—

82 B2c 3-pyridyl CN

HBr(1:1) 83 B2c 3-pyridyl CN

HCl(1:1) 84 B2c 3-pyridyl CN

HBr(1:1) 7 B2c 3-pyridyl CN

HBr(1:1) 8 B2d-1 3-pyridyl CN

85 B2a 3-pyridyl CH₃—O—C(═O)—

m.p.: 252- 254° C. 12 B2a 3-pyridyl CH₃—O—C(═O)—

HBr(1:1) 86 B2a 3-pyridyl CH₃—O—C(═O)—

87 B9 3-pyridyl CH₃CH₂—NH—CH₂—

88 B10 3-pyridyl

89 B8a 3-pyridyl

90 B8b 3-pyridyl CH₃

91 B8b 3-pyridyl (CH₃)₂N—CH₂—

92 B5 3-pyridyl H₂N—CH₂—

93 B5 3-pyridyl H₂N—CH₂—

95 B8b 3-pyridyl (CH₃)₂N—CH₂—

96 B2d-2 3-pyridyl CN

97 B1a

F

98 B1a 3-pyridyl F

99 B1b 3-pyridyl Br

100 B9 3-pyridyl

101 B9 3-pyridyl HO—CH₂—

Table 2 lists both the experimental (column heading “Exper”) andtheoretical (column heading “Theor”) elemental analysis values forcarbon (C), hydrogen (H) and nitrogen (N) for compounds as prepared inthe experimental part hereinabove.

TABLE 2 Co. C H N No. Theor Exper Theor Exper Theor Exper 62 46.17 45.803.15 2.83 10.09 9.85 4 46.87 47.32 2.10 2.05 14.58 14.31 1 53.10 53.162.67 2.54 12.38 12.18 30 63.14 62.98 4.24 4.03 14.73 14.54 27 50.4250.72 2.26 1.94 11.76 11.69 3 42.96 43.75 2.97 2.68 11.79 11.96 20 59.9159.45 3.84 3.72 16.44 16.29 25 53.97 53.19 2.66 2.68 14.81 14.28NMR Spectra Interpretation for Compounds 46 and 100.

Compound 46: ¹H NMR (360 MHz; DMSO-d6) d ppm 2.57 (s, 1H) 7.30 (d,J=7.68 Hz, 1H) 7.56 (t, J=7.96 Hz, 1H) 7.92 (d, J=9.51 Hz, 1H) 8.15 (m,2H) 8.82 (dt, J=8.37, 1.58 Hz, 1H) 8.89 (d, J=4.94 Hz, 1H) 9.15 (d,J=1.92 Hz, 1H) 10.73 (s, 1H).

Compound 100: ¹H NMR (360 MHz; DMSO-d6) d ppm 2.45 (m, 4H) 3.59 (t,J=4.30 Hz, 4H) 3.72 (s, 2H) 7.49 (t, J=9.40 Hz, 1H) 7.52 (ddd, J=7.89,4.83, 0.82 Hz, 1H) 7.90 (dt, J=8.76, 3.58 Hz, 1H) 8.05 (dt, J=7.91, 1.94Hz, 1H) 8.29 (dd, J=6.36, 2.79 Hz, 1H) 8.58 (dd, J=4.76, 1.65 Hz, 1H)8.89 (d, J=1.56 Hz, 1H) 10.59 (s, 1H).

C. Pharmacological Example Example C.1 In Vitro Inhibition of TNF-αProduction in Human Blood

Human Whole Blood Stimulation

Peripheral blood from healthy male donors was drawn into heparinizedsyringes (12.5 U heparin/ml). Blood samples were three-fold diluted inRMPI 1640 medium (Life Technologies, Belgium) supplemented with 2 mML-glutamine, 100 U/ml penicillin and 100 μg/ml streptomycin, and 300 μlfractions were distributed in 24-well multidisc plates (Nunc, Roskilde,Denmark). Blood samples were preincubated (60 minutes at 37° C.) in ahumidified 6% CO₂-atmosphere with 100 μl of drug solvent (finalconcentration 0.02% dimethylsulfoxide in RPMI 1640) or with 100 μl of anappropriate dose of test compound before being stimulated by theaddition of 100 μl of lipopolysaccharide at a final concentration of 100ng/ml. After 6 hours, cell-free supernatant fluids were collected bycentrifugation and stored at −20° C. until tested for the presence ofTNF-α.

Example C.2 In Vitro Inhibition of IL-12p40 Production in Human Blood

Human Whole Blood Stimulation

Peripheral blood from healthy male donors was drawn into heparinizedsyringes (12.5 U heparin/ml). Blood samples were three-fold diluted inRMPI 1640 medium (Life Technologies, Belgium) supplemented with 2 mML-glutamine, 100 U/ml penicillin and 100 μg/ml streptomycin, and 300 μlfractions were distributed in 24-well multidisc plates (Nunc, Roskilde,Denmark). Blood samples were preincubated (60 minutes at 37° C.) in ahumidified 6% CO₂-atmosphere with 100 μl of drug solvent (finalconcentration 0.02% dimethylsulfoxide in RPMI 1640) or with 100 μl of anappropriate dose of test compound before being stimulated by theaddition of 100 μl of lipopolysaccharide at a final concentration of 100ng/ml. After 24 hours, cell-free supernatant fluids were collected bycentrifugation and stored at −20° C. until tested for the presence ofIL-12p40.

Example C.3 Cytokine Measurements

Cytokine protein concentrations were determined by sandwich ELISA asdescribed in Van Wauwe et al. (1996, Inflamm Res, 45, 357-363). Murinemonoclonals used as capture antibodies to human cytokines were obtainedfrom R&D Systems (Abingdon, United Kingdom) and code named MAB210 andMAB611 for TNF-α and IL-12 respectively. Biotinylated goat polyclonalantibodies used to detect human cytokines were from R&D Systems (BAF210,BAF219). Cytokine levels were calculated from standard curves usingrecombinant cytokines supplied by R&D Systems.

Table 3 lists the percentage inhibition of TNF-α and IL-12 production(column “% inh”) at a test dose of 1×10⁻⁶ and 1×10⁻⁷ M for the compoundsof the present invention.

TABLE 3 % inhib. TNF-α % inhib. IL-12 (p40) Comp. No 1 × 10⁻⁶M 1 × 10⁻⁷M1 × 10⁻⁶M 1 × 10⁻⁷M 1 60 58 54 56 25 53 49 58 58 62 49 46 53 53 75 56 5232 51 14 52 4 57 27 58 3 49 20 51 46 44 23 48

1. A compound of formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof, wherein L isimidazothiazolyl; Q is C₃₋₆cycloalkyl, phenyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl,indazolyl, or imidazopyridyl, each of said rings optionally beingsubstituted with up to three substituents each independently selectedfrom halo; hydroxy; cyano; carboxyl; azido; amino; mono- ordi(C₁₋₆alkyl)amino; C₁₋₆alkylcarbonylamino; C₁₋₆alkyl; C₂₋₆alkenyl;C₂₋₆alkynyl; C₃₋₆cycloalkyl; C₁₋₆alkyl substituted with hydroxy,C₁₋₆alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino; C₁₋₆alkyloxy;C₁₋₆alkylthio; C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl;arylC₁₋₆alkyloxy; aryloxy; polyhaloC₁₋₆alkyl; polyhalo-C₁₋₆alkyloxy;polyhaloC₁₋₆alkylcarbonyl; piperidinylamino;1-methyl-4-piperidinylamino; morpholinyl, C₁₋₄alkyl-S(═O)_(n)— orH₂N—S(═O)_(n)—; and n is an integer of 1 or 2; or Q is a radical offormula

and wherein r is an integer from 1 to 3; q is an integer from 1 to 4; Xand Y are each independently O, NR³, CH₂ or S, with R³ being hydrogen orC₁₋₄alkyl; W is O or NR⁴, with R⁴ being hydrogen or C₁₋₄ alkyl; andwherein aryl is phenyl, optionally substituted with up to fivesubstituents each independently selected from halo, hydroxy, C₁₋₆alkyl,polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, cyano, nitro, amino ormono- or di(C₁₋₆alkyl)amino; and Z is halo; C₁₋₆alkyl; C₁₋₆alkylsubstituted with amino; C₁₋₆alkyl substituted with hydroxy;4-piperidinylaminomethyl; or 1-methyl-4-piperidinylaminomethyl.
 2. Acompound according to claim 1 wherein Q is benzthiazolyl; pyridylsubstituted with halo or C₁₋₆alkyl; phenyl or phenyl substituted withone, two or three substituents selected from halo, C₁₋₆alkyl,polyhaloC₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, hydroxy, C₁₋₆alkyloxy,C₁₋₆alkylthio, 1-methyl-2-imidazolyl; Z is halo; cyano;C₁₋₆alkylcarbonyl; aminocarbonyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl;C₁₋₆alkyl substituted with hydroxy, C₁₋₆alkyloxy, amino, mono- ordi(C₁₋₆alkyl)amino, piperidinylamino, 1-methyl-4-piperidinylamino ormorpholinyl.
 3. A pharmaceutical composition comprising apharmaceutically acceptable carrier and as active ingredient atherapeutically effective amount of a compound as claimed in claim
 1. 4.A pharmaceutical composition comprising a compound as defined in claim1, and another anti-inflammatory or immunosuppressive compound.
 5. Thecompound of claim 1 which